Cephalosporin derivatives

ABSTRACT

The invention relates to cephem derivatives of the general formula I &lt;IMAGE&gt;   and their physiologically acceptable acid addition salts, to pharmaceutical formulations active against bacterial infections, to processes for preparing the compounds and formulations, and to the use of the compounds for combating bacterial infections.

The invention relates to new cephalosporin derivatives and a process fortheir preparation, in particular to polar cephem derivatives which aresubstituted in the 3-position of the cephem ring by certainpyridiniummethyl radicals and which have a very good antimicrobialaction against Gram-positive and Gram-negative bacteria and which aretherefore suitable for use as medicaments for treating microbialinfections

The invention therefore relates to cephem derivatives of the generalformula I ##STR2## and to their physiologically acceptable acid additionsalts in which R¹ denotes hydrogen or halogen, R² denotes a group --CO₂R³ in which R³ denotes hydrogen, C₁ -C₄ -alkyl, --CH₂ OC₁ -C₄ -alkyl,--CH₂ OOC--C₁ -C₄ -alkyl or one equivalent of an alkali metal, alkalineearth metal, ammonium or of an organic amine base, a nitrile group or acarbamoyl group --CONH₂ which can be monosubstituted or disubstituted onthe nitrogen, l, m and n in each case denote 0 or 1, A denotes an arylradical, a group ##STR3## in which R⁴ and R⁵ can be identical ordifferent and form hydrogen, aryl, a C₁ -C₄ -alkyl group or, togetherwith the carbon to which they are bonded, a methylene or a C₃ -C₇-cycloalkylidene group, and alkyl and cycloalkyl can be furthermonosubstituted or polysubstituted, B denotes a pyridinium radical##STR4## which can be monosubstituted or polysubstituted by identical ordifferent substituents, namely by substituted C₁ -C₆ -alkyl, of which 2alkyl groups can also be linked to form a possibly substituted di- todeca-methylene ring in which a C atom can be replaced by a heteroatomand which can additionally contain one or two double bonds, by cyano-C₁-C₃ -alkyl, epoxy-C₂ -C₆ -alkyl, trifluoromethyl or pentafluoroethyl, byhydroxyiminomethyl or C₁ -C₄ -alkoxyiminomethyl, by optionallysubstituted C₂ -C₆ -alkenyl, by C₂ -C₆ -alkynyl, by C₃ -C₇ -cycloalkylor C₃ -C₇ -cycloalkylmethyl, in which two substituents the ring can alsobe substituted and in which a C atom can be replaced by a heteroatom, byC₄ -C₇ -cycloalkenyl, by optionally substisubstituted, by C₄ -C₇-cycloalkenyl, by optionally substituted C₁ -C₆ -alkoxy, by epoxy-C₂ -C₆-alkenyloxy or C₂ -C₆ -alkynyloxy, by halogen, cyano, hydroxyl ormercapto, by C₁ -C₆ -alkysulfonyl, C₁ -C₆ -alkylsulfinyl or C₁ -C₆-alkylthio which is optionally substituted in the alkyl part, bymethylsulfonyl, methylsulfinyl or methylthio which is substituted on themethyl radical, by C₂ -C₆ -alkenylthio, C₂ -C₆ -alkenylsulfinyl or C₂-C₆ -alkenylsulfonyl, by optionally substituted phenyl, benzyl orheteroaryl, by formyl or ketalized formyl, by optionally substituted C₁-C₆ -alkylcarbonyl which can also be present in ketalized form, byarylcarbonyl, by C₁ -C₆ -alkylcarbonylamino, by carboxyl or C₁ -C₆-alkoxycarbonyl, by carbamoyl, which can be monosubstituted ordisubstituted on the nitrogen, by optionally substituted carbazoyl, bysulfamoyl, which can be monosubstituted on the nitrogen, or by pyridylor 4-pyridon-1-yl, and in which the group --O--(CH₂)_(n) (A)_(m) R² isin the syn position.

The present invention relates in particular to compounds in which R¹,R², A, l, n and m have the abovementioned meanings and B denotes apyridinium radical ##STR5## which can be 1-substituted orpolysubstituted by identical or different substituents, namely by C₁ -C₆-alkyl which can be monosubstituted or polysubstituted by hydroxyl,carboxyl, C₁ -C₆ -alkyloxycarbonyl, formyl or C₁ -C₆ -alkylcarbonyl, thecarbonyl groups of which can also be present in ketalized form,carbamoyl, N-hydroxycarbamoyl, sulfo, C₁ -C₆ -alkyloxy, hydroxy-C₁ -C₆-alkyloxy, C₁ -C₆ -alkylthio, C₁ -C₆ -alkylsulfinyl, C₁ -C₆-alkylsulfonyl, C₂ -C₆ -alkenyloxy, C₂ -C₆ -alkenylthio, C₂ -C₆-alkenylsulfinyl or C₂ -C₆ -alkenylsulfonyl, and of which 2 alkyl groupscan also be linked to form an optionally substituted di- todeca-methylene ring in which a C atom can be replaced by a heteroatomand which can additionally contain one or two double bonds, by cyano-C₁-C₃ -alkyl, epoxy-C₂ -C₆ -alkyl, trifluoromethyl, hydroxyiminomethyl orC₁ -C₄ -alkoxyiminomethyl, pentafluoroethyl, by C₂ -C₆ -alkenyl whichcan be substituted by hydroxyl, by C₂ -C₆ -alkynyl, by C₃ -C₇-cycloalkyl or C₃ -C₇ -cycloalkylmethyl, in which two substituents thering can also be substituted by hydroxyl, halogen, carboxyl, C₁ -C₆-alkyloxycarbonyl or cyano and in which a C atom can be replaced by anoxygen atom, by C₄ -C₇ -cycloalkenyl, by C₁ -C₆ -alkoxy, which can besubstituted by hydroxyl, carboxyl or C₁ -C₆ -alkyloxycarbonyl, byepoxy-C₂ -C₆ -alkoxy, by C₂ -C₆ -alkenyloxy or C₂ -C₆ -alkynyloxy, byhalogen, cyano, hydroxyl or mercapto, by C₁ -C₆ -alkylthio, C₁ -C₆-alkylsulfinyl or C₁ -C₆ -alkylsulfonyl, all of which can be substitutedby hydroxyl in the alkyl part, by methylthio, methylsulfinyl ormethylsulfonyl, all of which are substituted in the methyl part bycarboxyl or C₁ -C₆ -alkyloxycarbonyl, by C₂ -C₆ -alkenylthio, C₂ -C₆-alkenylsulfinyl or C₂ -C₆ -alkenylsulfonyl, by phenyl, benzyl orheteroaryl, all of which can also be substituted by halogen, by formylor ketalized formyl, by C₁ -C₆ -alkylcarbonyl which can also besubstituted by hydroxyl and can also be present in ketalized form, byarylcarbonyl or C₁ -C.sub. 6 -alkylcarbonylamino, by carboxyl or C₁ -C₆-alkoxycarbonyl, by carbamoyl which can be monosubstituted on thenitrogen by C₁ -C₆ -alkyl, hydroxy-C₁ -C₆ -alkyl, C₁ -C₆-alkyloxycarbonyl, C₁ -C₆ -alkylcarbonyl, carboxymethyl, C₁ -C₆-alkyloxycarbonylmethyl, aminocarbonylmethyl, C₁ -C₆-alkylaminocarbonyl, carbamoyl, hydroxyl or pyridyl, or which can bedisubstituted on the nitrogen by C₁ -C₆ -alkyl, by carbazoyl which canbe substituted by C₁ -C₄ -alkyl, or N-carbamoylcarbazoyl, by sulfamoylwhich can be monosubstituted on the nitrogen by C₁ -C₆-alkylaminocarbonyl, or by pyridyl or 4-pyridon-1-yl, and in whichpreferred compounds of the general formula I the R² (A)_(m) (CH₂)_(n)O-- group is also in the syn position.

Optionally possible substituents for the di- to deca-methylene ringmentioned under B, in which a C atom can be replaced by a heteroatom andone or two double bonds can additionally be contained, are in particularthe following substituents, which can occur once or several times butpreferably occur once: C₁ -C₆ -alkyl, C₁ -C₄ -alkoxy, hydroxymethyl,halogen, hydroxyl, oxo, hydroxyimino, exomethylene, carboxyl, C₁ -C₆-alkyloxycarbonyl, cyano or carbamoyl.

These substituents can occur in the rings which have been mentioned andare fused onto the pyridinium radical, regardless of whether theparticular ring is saturated, unsaturated, or additionally, interruptedby a heteroatom. However, according to the invention the substituentspreferably occur on fused-on saturated rings which do not contain anyheteroatoms.

The ring fused on the pyridinium radical can contain 2 to 10 ringmembers (di- to deca-methylene), but it preferably contains 3 to 5 ringmembers and it can thus be, for example, a cyclopenteno, cyclohexeno orcyclohepteno ring. If such a fused-on ring contains a double bond, thenexamples which may be mentioned are a cyclopentadieno, cyclohexadieno orcycloheptadieno ring. If in such rings a C atom is replaced by aheteroatom, the latter can be in particular oxygen or sulfur. Exampleswhich may be mentioned of fused-on rings which contain an oxygen atomand two or one double bonds are furo, pyrano, dihydrofuro anddihydropyrano, and examples of fused-on rings which have a sulfur atomand contain two or one double bonds are thieno, thiopyrano,dihydrothieno and dihydrothiopyrano. Among the fused-on rings whichcontain a heteroatom, candidates of a substitution, in particular by theabovementioned substituents, are in particular those rings which containonly one double bond.

Examples of particularly preferable substituents are: R₁ : hydrogen,bromine, chlorine and fluorine, in particular chlorine and bromine, R₂ :the group --CO₂ R³ in which R³ denotes hydrogen, C₁ -C₄ -alkyl, such as,for example, methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl,tert.-butyl, preferably methyl, ethyl, in particular methyl, or oneequivalent of an alkali metal, such as, for example, sodium, potassium,lithium, preferably sodium and potassium, one equivalent of an alkalineearth metal, preferably calcium or magnesium, of ammonium, and oneequivalent of an organic amine base, such as, for example,trimethylamine, diethylamine, triethylamine, methylamine, propylamine,N,N-dimethylethanolamine, tris(hydroxymethyl)-aminomethane, arginine orlysine, a nitrile group, a carbamoyl group which can be monosubstitutedat the nitrogen by C₁ -C₆ -alkyl, hydroxy-C₁ -C₆ -alkyl, C₁ -C₆-alkyloxycarbonyl, C₁ -C₆ -alkylcarbonyl, carboxymethyl, C₁ -C₆-alkyloxycarbonylmethyl, aminocarbonylmethyl, C₁ -C₆-alkylaminocarbonyl, carbamoyl, hydroxyl, C₁ -C₆ -alkyloxy or which canbe disubstituted at the nitrogen by C₁ -C₆ -alkyl, A: an aryl radical,preferably a phenyl radical, the group ##STR6## in which R⁴ and R⁵ canbe identical or different and can denote hydrogen, aryl, preferablyphenyl, C₁ -C₄ -alkyl, such as, for example, methyl, ethyl, propyl,isopropyl, butyl, sec.-butyl, preferably methyl, ethyl, in particularmethyl, or in which R⁴ and R⁵, together with the carbon atom to whichthey are bonded, can form a methylene group or a C₃ -C₇ -cycloalkylidenegroup, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, preferably cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl, and in which the cycloalkylidene group can besubstituted, for example by C₁ -C₄ -alkyl, preferably methyl, byhalogen, preferably fluorine and chlorine, or can also be substituted byalkylene having 3-6C atoms, l=0 or 1, preferably 0, m=0 or 1, n=0 or 1,with the sum of m and n being 1 or 2.

Preferable examples of the group --(CH₂)_(n) (A)_(m) -- are thefollowing:

In the event that n=0 and m=1: ##STR7## in the event that m=0 and n=1:--CH₂ --, and if n and m=1: ##STR8## B: a pyridinium radical which canbe monosubstituted or polysubstituted, preferably 1- to 3-fold, inparticular 1- to 2-fold, for example by C₁ -C₄ -alkyl, such as, inparticular, methyl, ethyl, propyl, isopropyl, n-butyl, sec.-butyl,tert.-butyl, dimethyl, trimethyl, methyl and ethyl, methyl and propyl,methyl and isopropyl, ethyl and ethyl, hydroxy-C₁ -C₄ -alkyl, such as inparticular, hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxyisopropyl, hydroxybutyl, hydroxy-sec.-butyl orhydroxy-tert.-butyl, and in which it is also possible, for example, fortwo or three hydroxyl groups to be present on the alkyl radical,carboxy-C₁ -C₄ -alkyl, such as, in particular, carboxymethyl andcarboxyethyl, C₁ -C₄ -alkyloxycarbonyl-C₁ -C₄ -alkyl, such as, inparticular, methyloxycarbonylmethyl, ethyloxycarbonylmethyl,methyloxycarbonylethyl, formyl-C₁ -C₄ -alkyl, such as in particular,formylmethyl, C₁ -C₄ -alkylcarbonyl-C₁ -C₄ -alkyl, such as, inparticular, methylcarbonylmethyl, ethylcarbonylmethyl,methylcarbonylethyl and ethylcarbonylethyl, the two alkyl groups ofwhich can also be further substituted by hydroxyl and the carbonyl groupof which can also be present in the ketalized form, carbamoyl-C₁ -C₄-alkyl, such as, in particular, carbamoylmethyl and carbamoylethyl,which can also be further substituted by hydroxyl on the nitrogen, suchas, in particular, N-hydroxycarbamoylmethyl, sulfo-C₁ -C₄ -alkyl, suchas, in particular, sulfoethyl or 1-hydroxy-1-sulfomethyl, C₁ -C₄-alkyloxy-C₁ -C₄ -alkyl, such as, in particular, methoxymethyl,ethoxymethyl, propoxymethyl, isopropoxymethyl, methoxyethyl,ethoxyethyl, methoxypropyl and methoxyisopropyl, all of which can alsobe substituted by hydroxyl, such as, in particular, hydroxyethoxymethyland hydroxyethoxyethyl, C₁ -C₄ -alkylthio-C₁ -C₄ -alkyl, such as, inparticular, methylthiomethyl, ethylthiomethyl, methylthioethyl andethylthioethyl, C₁ -C₄ -alkylsulfinyl-C₁ 14 C₄ -alkyl, such as, inparticular, methylsulfinylmethyl, ethylsulfinylmethyl,methylsulfinylethyl and ethylsulfinylethyl, C₁ -C₄ -alkylsulfonyl-C₁ -C₄-alkyl, such as, in particular, methylsulfonylmethyl,ethylsulfonylmethyl, methylsulfonylethyl and ethylsulfonylethyl, C₃-alkenyloxy-C₁ -C₄ -alkyl, such as, in particular, allyloxymethyl andallyloxyethyl, C₃ -alkenylthio-C₁ -C₄ -alkyl, such as, in particular,allylthiomethyl, C₃ -alkenylsulfinyl-C₁ -C₄ -alkyl, such as, inparticular, allylsulfinylmethyl, C₃ -alkenylsulfonyl-C₁ -C₄ -alkyl, suchas, in particular, allylsulfonylmethyl, cyano-C₁ -C₃ -alkyl, such as, inparticular, cyanomethyl and cyanoethyl, epoxy-C₂ -C₃ -alkyl, such as, inparticular, epoxyethyl and epoxypropyl, trifluoromethyl,hydroxyiminomethyl and C₁ -C₃ -alkoxyiminomethyl, such as, inparticular, methoxyiminomethyl, C₃ -C₄ -alkenyl, such as, in particular,allyl, 2-methylallyl and buten-3-yl, all of which can also be furthersubstituted by hydroxyl, such as, in particular, hydroxyallyl andhydroxybutenyl, C₃ -alkynyl, such as, in particular, propargyl, C₃ -C₆-cycloalkyl and C₃ -C₆ -cycloalkylmethyl, in which the number of carbonsrelates to the cycloalkyl part, such as, in particular, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cyclopentylmethyl, in which therings can also be substituted, for example, by hydroxyl, such as, inparticular, 1-hydroxy-1-cyclopentyl and 1-hydroxy-1-cyclohexyl, or byhalogen, preferably chlorine, by carboxyl, C₁ -C₄ -alkoxycarbonyl orcyano, C₅ -C₆ -cycloalkenyl, such as, in particular, cyclopenten-1-yland cyclohexen-1-yl, C₁ -C₄ -alkoxy, such as, in particular, methoxyethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert.-butoxy,preferably methoxy, all of which alkoxy groups can also be furthersubstituted, for example, by hydroxyl, carboxyl or C₁ -C₄-alkoxycarbonyl, in particular carboxymethoxy andmethoxycarbonylmethoxy, epoxy-C₂ -C₃ -alkoxy, such as, in particular,epoxyethoxy or epoxypropoxy, C₃ -alkenyloxy, such as, in particular,allyloxy, C₃ -alkynyloxy, such as, in particular, propargyloxy, halogen,such as, in particular, fluorine, chlorine, bromine or iodine, cyano,hydroxyl, in particular 3-hydroxy, C₁ -C₄ -alkylthio, such as, inparticular, methylthio, ethylthio, propylthio and isopropylthio, all ofwhich can also be substituted by hydroxyl, in particularhydroxyethylthio, C₁ -C₄ -alkylsulfinyl, such as, in particular,methylsulfinyl, ethylsulfinyl, propylsulfinyl and isopropylsulfinyl, allof which can also be substituted by hydroxyl, in particularhydroxyethylsulfinyl, C₁ -C₄ -alkylsulfonyl, such as methylsulfonyl,ethylsulfonyl, propylsulfonyl or isopropylsulfonyl, all of which canalso be substituted by hydroxyl, in particular hydroxyethylsulfonyl,carboxymethylthio and C₁ -C₄ -alkoxycarbonylmethylthio, in particularmethoxycarbonylmethylthio, carboxymethylsulfinyl andcarboxymethylsulfonyl, C₁ -C₄ -alkoxycarbonylmethylsulfinyl and-alkoxycarbonylmethylsulfonyl, in particularmethoxycarbonylmethylsulfinyl and methoxycarbonylmethylsulfonyl, C₃-alkenylthio, such as allylthio and propen-1-ylthio, C₃-alkenylsulfinyl, such as allylsulfinyl and propen-1-ylsulfinyl, C₃-alkenylsulfonyl, such as allylsulfonyl and propen-1-ylsulfonyl, phenyland benzyl, both of which can also be substituted, for example byhalogen, in particular chlorine, such as, for example, 4-chlorobenzyl,2'-thienyl and 3'-thienyl, formyl and ketalized formyl, such as, forexample, 1,3-dioxolan-2-yl, C₁ -C₄ -alkylcarbonyl, in particular acetyland propionyl, preferably acetyl, which can also be substituted byhydroxyl and be present in ketalized form, such as, for example,2-methyl-1,3-dioxolan-2-yl, benzoyl, C₁ -C₄ -alkylcarbonylamino, inparticular acetylamino and propionylamino, formylamino, carboxyl, forexample also 2,3,4-carboxyl, C₁ -C₄ -alkoxycarbonyl, in particularmethoxycarbonyl and ethoxycarbonyl, such as, for example, also2,3,4-methoxycarbonyl or 2,3,4-ethoxycarbonyl, carbamoyl (for examplealso 2,3,4-carbamoyl) which can be monosubstituted on the nitrogen atomby C₁ -C₄ -alkyl, such as, in particular, N-methylcarbamoyl andN-ethylcarbamoyl, by hydroxy-C₁ -C₄ -alkyl, such as, in particular,N-hydroxymethylcarbamoyl and N-hydroxyethylcarbamoyl, by C₁ -C₄-alkoxycarbonyl, such as, in particular, N-methoxycarbonylcarbamoyl andN-ethoxycarbonylcarbamoyl, by C₁ -C₄ -alkylcarbonyl, such as, inparticular, N-acetylcarbamoyl, by carboxymethyl, by C₁ -C₄-alkoxycarbonylmethyl, such as in particular,N-methoxycarbonylmethylcarbamoyl and N-ethoxycarbonylmethylcarbamoyl, byaminocarbonylmethyl, by N-C₁ -C₄ -alkylaminocarbonyl, such as, inparticular, N-methylaminocarbonylcarbamoyl andN-ethylaminocarbonylcarbamoyl by carbamoyl (=ureidocarbonyl), byhydroxyl or pyridyl, such as, in particular, N-3'-pyridylcarbamoyl andN-4'-pyridylcarbamoyl, N-C₁ -C₄ -dialkylcarbamoyl, such as, inparticular, N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl, carbazoylwhich can be substituted by C₁ -C₄ -alkyl, in particular methyl orethyl, by carbamoyl, such as N-carbamoylcarbazoyl, sulfamoyl, which canbe substituted on the nitrogen atom by C₁ -C₄ -alkylaminocarbonyl, suchas, in particular, ethylaminocarbonylsulfamoyl, and pyridyl, such as, inparticular, 2'-, 3'- and 4'-pyridyl and 4-pyridon-1-yl.

If B represents a pyridinium radical which is substituted by two alkylgroups which are linked to form a di- to deca-methylene ring which inturn can be monosubstituted or polysubstituted but preferably ismonosubstituted and can contain one or two double bonds, examples ofthis are in particular the following fused-on ring systems:cyclopenteno, hydroxycyclopenteno, chlorocyclopenteno,bromocyclopenteno, oxocyclopenteno, hydroxymethylcyclopenteno,exomethylenecyclopenteno, carboxycyclopenteno, C₁ -C₄-alkoxycarbonylcyclopenteno, in particular methoxycarbonylcyclopentenoand carbamoylcyclopenteno, cyclohexeno, hydroxycyclohexeno,chlorocyclohexeno, bromocyclohexeno, oxocyclohexeno,hydroxymethylcyclohexeno, exomethylenecyclohexeno, carboxycyclohexeno,C₁ -C₄ -alkoxycarbonylcyclohexeno, in particularmethoxycarbonylcyclohexeno and carbamoylcyclohexeno, cyclohepteno,hydroxy-, chloro-, bromo-, oxo-, hydroxymethyl-, exomethylene- orcarboxy-cyclohepteno, C₁ -C₄ -alkoxycarbonylcyclohepteno, in particularmethoxycarbonylcyclohepteno and carbamoylcyclohepteno, cyclopentadieno,cyclohexadieno and cycloheptadieno.

If in the abovementioned fused-on ring systems a C atom is replaced by aheteroatom, in particular oxygen or sulfur, possible examples are inparticular: 2,3- and 3,4-furo, 2,3- and 3,4-pyrano, 2,3- and3,4-dihydrofuro, 2,3- and 3,4-dihydropyrano, methyldihydrofuro,methoxydihydropyrano and hydroxydihydropyrano.

The invention also relates to a process for preparing compounds of theformula I and their physiologically acceptable acid addition salts,which process comprises reacting (a) a compound of the general formulaII ##STR9## in which R¹, A, l, n and m have the abovementioned meaningsand R² has the abovementioned meaning and in which, in the group --CO₂R³, R³ has the abovementioned meaning, or denotes an ester group readilydetachable by acidic hydrolysis or hydrogenolysis, R⁶ denotes hydrogenor an amino protective group, R⁷ denotes a group which can be replacedby pyridine or substituted pyridines which correspond to the pyridiniumradicals B of the formula I, and R⁸ denotes a hydrogen atom or oneequivalent of an alkali metal, alkaline earth metal, ammonium or of anorganic amine base, with pyridine or a pyridine derivative which is suchthat it corresponds to one of the pyridinium radicals B mentioned in theformula I, whereupon, if the radicals R³ and R⁶ denote theabovementioned readily detachable groups, the latter are eliminated bytreatment with an agent for acidic hydrolysis or hydrogenolysis or withthiourea and compounds of the formula I are thus obtained, or (b)reacting a 7-aminocephem compound of the general formula III ##STR10##in which B has the meaning mentioned in the formula I, or its acidaddition salts, in which the amino group can also be present in the formof a reactive derivative with a2-(2-aminothiazol-4-yl)-2-syn-oximinoacetic acid of the general formulaIV ##STR11## in which R¹, R², R⁶, A, n and m have the abovementionedmeaning and in which, if R₂ represents COOR³, R³ has the abovementionedmeaning or denotes an ester group readily detachable by acidichydrolysis or hydrogenolysis, with an activated derivative of thiscompound and (α) eliminating a protective group, if present and (β) ifnecessary, converting the product obtained into a physiologicallyacceptable acid addition salt.

If the compounds of the general formula I are to be prepared by anucleophilic replacement reaction of R⁷ in the compounds of the generalformula II by pyridine or one of the pyridine derivatives indicated,possible examples of radicals R⁷ are in particular acyloxy radicals oflower aliphatic carboxylic acids, preferably having 1 to 4C atoms, suchas, for example, acetoxy or propionyloxy, in particular acetoxy, whichradicals may be substituted, such as, for example, chloroacetoxy oracetylacetoxy. Other groups are also possible for R⁷ such as, forexample, halogen, in particular chlorine or bromine, or carbamoyloxy.

Starting compounds of the general formula II in which R⁷ representsacetoxy, or their salts, such as, for example, a sodium salt orpotassium salt, are used, according to the invention, in thenucleophilic replacement reaction. The reaction is carried out in asolvent, preferably in water, or in a mixture of water and an organicsolvent which is readily miscible with water, such as, for example,acetone, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide orethanol. The reaction temperature is in general within the range fromabout 10° to about 100° C., preferably between 20° and 80° C. Thepyridine component is added in amounts which are between approximatelyequimolar amounts and not more than an approximately 5-fold excess. Thereplacement of the radical R⁷ is facilitated by the presence of neutralsalt ions, preferably of iodide or thiocyanate ions, in the reactionmedium. In particular, about 10 to about 30 equivalents of potassumiodide, sodium iodide, potassium thiocyanate or sodium thiocyanate areadded. The reaction is advantageously carried out under approximatelyneutral conditions, preferably at a pH value within the range from about5 to about 8.

If R⁷ represents a carbamoyl group, the replacement reaction is carriedout analogously. If R⁷ represents halogen, in particular bromine, thereplacement is effected in a manner described in the literature.

If the compounds of the formula II contain amino or acid protectivegroups in the radicals R³ and R⁶, the protective groups are eliminatedafter the nucleophilic replacement in a way which is in itself known byacidic hydrolysis, by hydrogenolysis or by means of thiourea.

Ester groups R³ readily detachable by acidic hydrolysis orhydrogenolysis include, for example, tert.-butyl, tert.-amyl, benzyl,p-methoxybenzyl, p-nitrobenzyl and trichloroethyl. Examples of suitableamino protective groups R⁶ are optionally substituted alkyl, such as,for example, tert.-butyl, tert.-amyl, benzyl, p-methoxybenzyl, trityl,benzhydryl, preferably trityl, trialkylsilyl, such as, for example,trimethylsilyl, optionally substituted aliphatic acyl, such as, forexample, formyl, chloroacetyl, bromoacetyl, trichloroacetyl andtrifluoroacetyl, preferably chloroacetyl, or optionally substitutedalkoxycarbonyl, such as, for example, trichloroethoxycarbonyl,benzyloxycarbonyl, or tert.-butoxycarbonyl, preferablytert.-butoxycarbonyl and benzyloxycarbonyl, as well as2-tetrahydropyranyl.

The acylation of the compounds of the general formula III or of theiraddition salts, for example with hydrochloric acid, hydrobromic acid,nitric acid, phosphoric acid or an organic acid, such as, for example,methanesulfonic acid or p-toluenesulfonic acid, can be carried out bymeans of carboxylic acids of the general formula IV or by means of areactive derivative of such an acid. In this step, it is in some casesadvantageous to protect the 2-amino group in the compounds of thegeneral formula IV from the reaction by means of the abovementionedamino protective groups R₆.

After the acylation, the protective group can be split off in a mannerwhich is in itself known, for example the trityl group by means of acarboxylic acid, such as, for example acetic acid, trifluoroacetic acidor formic acid, or the chloroacetyl group by means of thiourea.

If the carboxylic acids of the general formula IV and their derivativesprotected at the amino group are themselves used as acylating agents,the reaction is advantageously carried out in the presence of acondensing agent, for example of a carbodiimide, such as, for example,N,N'-dicyclohexylcarbodiimide.

The activation of the carboxylic acid of the general formula IV can beparticularly advantageously effected by treatment with certaincarboxamides and, for example, phosgene, phosphorus pentachloride, tosylchloride, thionyl chloride or oxalyl chloride, as described in GermanPatent No. 2,804,040.

Suitable activated derivatives of the carboxylic acids of the generalformula IV are in particular also halides preferably chlorides, whichcan be obtained in a manner which is in itself known by treatment withhalogenating agents, such as, for example, phosphorus pentachloride,phosgene or thionyl chloride, under mild reaction conditions describedin cephalosporin chemistry literature.

Further suitable activated derivatives of the carboxylic acids of thegeneral formula IV are the anhydrides and mixed anhydrides, azides andactivated esters, preferably those formed with p-nitrophenol,2,4-dinitrophenol, methylenecyanohydrin, N-hydroxysuccinimide andN-hydroxyphthalimide, in particular those formed with1-hydroxybenzotriazole and 6-chloro-1-hydroxybenzotriazole. Particularlysuitable mixed anhydrides are those formed with lower alkanoic acids,such as, for example, acetic acid, and particularly preferably thoseformed with substituted acetic acids, such as, for example,trichloroacetic acid, pivalic acid or cyanoacetic acid. However, thosemixed anhydrides are also particularly suitable which are formed withcarbonic acid half-esters, which are obtained, for example, by reactingthe carboxylic acids of the formula IV, in which the amino group isprotected, with benzyl chloroformate, p-nitrobenzyl chloroformate,isobutyl chloroformate, ethyl chloroformate or allyl chloroformate. Theactivated derivatives can be reacted as isolated substances or in situ.

Generally, the reaction of the cephem derivatives of the general formulaIII with a carboxylic acid of the general formula IV or with anactivated derivative thereof is carried out in the presence of an inertsolvent. Particularly suitable solvents are chlorinated hydrocarbons,such as preferably methylene chloride and chloroform, ethers, such as,for example, diethyl ether, preferably tetrahydrofuran and dioxane,ketones, such as preferably acetone and butanone, amides, such aspreferably dimethylformamide and dimethylacetamide, or water. It canalso be advantageous to use mixtures of the solvents mentioned. This canbe advantageous in many cases where the cephem compound of the generalformula III is reacted with an activated derivative of a carboxylic acidof the formula IV which derivative has been formed in situ.

The reaction of cephem compounds of the formula III with carboxylicacids of the formula IV or with activated derivatives thereof can becarried out within a temperature range of about 31 80° to about +80° C.,preferably between -30° and +50° C., but in particular between about-20° C. and room temperature.

The reaction time depends on the reactants, the temperature and themixture of solvents and normally is between about 1/4 and about 72hours.

The reaction with acid-halides may be carried out in the presence of anacid-binding agent to bind the hydrogen halide liberated. Suitableacid-binding agents are in particular tertiary amines, such as, forexample, triethylamine or dimethylaniline, inorganic bases, such as, forexample, potassium carbonate or sodium carbonate, or alkylene oxides,such as, for example, propylene oxide. The presence of a catalyst, suchas, for example, of dimethylaminopyridine, may also be advantageous.

If in the compounds of the general formula III the amino group ispresent in the form of a reactive derivative, the latter can be of atype described in the literature for amidations. Possible examples arethus silyl derivatives which are formed when compounds of the generalformula III are reacted with a silyl compound, such as, for example,trimethylchlorosilane or bis-(trimethylsilyl)-acetamide. If the reactionis carried out with one of these compounds which are activated at theamino group, it is advantageous to carry out the reaction in an inertsolvent, such as, for example, methylene chloride, tetrahydrofuran ordimethylformamide.

Sulfoxides of the general formula I (l=1) are isolated in a manner whichis in itself known by oxidation from cephalosporin derivatives of thegeneral formula I in which l=0.

Suitable for the oxidation of the sulfur in the cephem ring are, forexample, the methods described in the literature and which lead to theformation of SO and SO₂ bonds by oxidation of sulfides, as described,for example, in Methodicum Chimicum, volume 7 (1976),Hauptgruppenelemente und deren Verbindungen [Main group elements andtheir compounds], pages 693-698, by F. Korte, and the oxidizing agentsmentioned in E. F. Flynn, Cephalosporins and Penicillins, Chemistry andBiology, Academic Press, New York and London, 1972, preferably thelight-sensitized oxidation by means of oxygen, peroxides,hydroperoxides, peracids, singlet oxygen, hydrogen peroxide and mixturesthereof with inorganic or organic oxidation-resistant acids, such as,for example, phosphoric acid, formic acid, acetic acid ortrifluoroacetic acid. The peracids can also be produced in situ bymixing of the acids with hydrogen peroxide. 3-Chloroperbenzoic acid isadvantageously used directly.

Suitable solvents for the oxidation are all solvents stable under thereaction conditions, such as, for example, dioxane, tetrahydrofuran,chloroform, methylene chloride, acetic acid, formic acid,trifluoroacetic acid, glycol dimethyl ether, benzene, chlorobenzene,tetramethylurea, dimethylformamide and dimethylacetamide.

The reaction conditions and the amount of oxidizing agent depend on thefinal product desired and on the substituents present on the cephemskeleton. To prepare R- and S-sulfoxides, 2 oxidation equivalents(corresponding to one active oxygen atom) or a small excess aresufficient.

The reaction temperatures can be between about -20° and +80° C., but theoxidation is carried out at as low a temperature as possible, preferably-20° C. to +20° C.

In the oxidation of compounds of the formula I in which l represents 0it is generally known that in the case of 7-acylaminocephem derivativessulfoxides having S-configuation are predominantly formed.

R- and S-sulfoxides are separated and characterized owing to theirdiffering solubility and their differing migration rate inchromatographic separations. A further distinction between R- andS-sulfoxides can be made with the aid of NMR spectroscopy (cf. theabovementioned reference by E. H. Flynn).

Physiologically acceptable acid addition salts of compounds of thegeneral formula I which may be mentioned by way of example are thosesalts formed with hydrochloric acid, hydrobromic acid, nitric acid,phosphoric acid or with organic acids, such as, for example,methanesulfonic acid or o-toluenesulfonic acid or maleic acid.

Compounds of the general formula III can be obtained in a manner whichis in itself known, for example from 7-aminocephalosporanic acidprotected at the amino group, in the way as described above for thenucleophilic replacement of R⁷.

Compounds of the general formula IV and the pyridine derivatives whichcorrespond to the pyridinium radicals B are known from the literature orcan be prepared by methods described in the literature.

Compounds of the general formula I, obtained according to the invention,and their physiologically acceptable acid addition salts have remarkablyhigh antibacterial actions, not only against Gram-positive but alsoagain Gram-negative bacterial germs.

The compounds of the formula I are also unexpectedly highly activeagainst penicillinase- and cephalosporinase-forming bacteria. Sincethese compounds additionally have favorable toxicological andpharmacological properties, they are valuable chemotherapeutic agents.

The invention thus also relates to medicaments for treating microbialinfections and which contain one or more of the compounds according tothe invention.

The products according to the invention can also be used in combinationwith other active compounds, for example of the series of thepenicillins, cephalosporins or aminoglycosides.

The compound of the general formula I and their physiologicallyacceptable acid addition salts can be administered orally,intramuscularly or intravenously. Medicaments which contain one or morecompounds of the general formula I as active compound can be prepared bymixing the compounds of the formula I with one or more pharmacologicallyacceptable excipients or diluents, such as, for example, fillers,emulsifiers, lubricants, taste corrigents, colorants or buffersubstances and bringing the mixtures into a suitable galenicadministration form, such as, for example, tablets, coated tablets,capsules or a solution or suspension suitable for parenteraladministration.

Examples which may be mentioned of excipients or diluents aretragacanth, lactose, talc, agar-agar, polyglycols, ethanol and water.Preferaby suspensions or solutions in water are used for parenteraladministration. It is also possible to administer the active compoundsas such, without excipients or diluents, in a suitable form, for examplein capsules.

Suitable doses of compounds of the general formula I or of theirphysiologically acceptable acid addition salts are from about 0.1 to 20g per day, preferably 0.5 to 4 g per day, for an adult weighing about 60kg.

Single, or in general, multiple doses can be administered, and thesingle dose can contain the active compound in an amount from about 50to 1,000 mg, preferably from about 100 to 500 mg.

Cephem compounds of the formula I in which R₁ represents hydrogen, lrepresents 0, B represents pyridinium and --(CH₂)_(n) (A)_(m) R²represents --CH₂ COOR' (R'=H or C₁₋₄ alkyl) are known from GermanOffenlegungsschrift No. 3,037,101, while those with R₁ =H, l=0,B=pyridinium or 3- or 4-carbamoylpyridinium and a radical ##STR12## atthe oximino group (with R_(a),b =C₁₋₄ -alkyl or C₃₋₇ -cycloalkylidene)are known from German Offenlegungsschrift No. 2,921,316.

In addition to the products described in the illustrative examples, itis also possible to prepare, according to the invention, compounds whichcorrespond to the general formula I' ##STR13## in which the radical--(CH₂)_(n) (A)_(m) R² has the abovementioned meaning, preferably thefollowing meanings ##STR14## and is in the syn-position, and B' (a)represents a pyridinium radical substituted by the radicals indicated inTable 1 or (b) denotes one of the radicals shown in Table 2.

In the formula I', the meanings of B' to be taken from Table 1 and 2would thus have to be combined in each case in particular with theradicals mentioned above as preferable for --(CH₂)_(n) (A)_(m) R². Onlyfor reasons of space has the replication of Tables 1 and 2, in itselfnecessary for each of these radicals of the oxime group, been omitted.

In Table 1, the numbers show the position of the substituent(s) on thepyridinium radical.

                                      TABLE 1                                     __________________________________________________________________________    2,3-di-CH.sub.3 2,5-di-CH.sub.3 2-Propyl                                                    3-Cyclobutyl 4-Cyclobutyl 2-Cyclopentyl                                                      ##STR15##                                        3-Propyl 2-Isopropyl 2-n-Butyl                                                              3-Cyclopentyl 4-Cyclopentyl 2-Cyclopentylmethyl                                              ##STR16##                                        3-n-Butyl 4-n-Butyl 2-sec-Butyl 3-sec-Butyl                                                 3-Cyclopentylmethyl 4-Cyclopentylmethyl 2-Cyclohexyl                          3-Cyclohexyl                                                                                 ##STR17##                                        4-sec-Butyl   4-Cyclohexyl  2-CH.sub.2 OH3-CH.sub.3                           2-tert-Butyl  2-Cyclopentyl-3-CH.sub.3                                                                    2-CH.sub.2 OH4-CH.sub.3                           3-tert-Butyl  2-Cyclopentyl-4-CH.sub.3                                                                    2-CH.sub.2 OH5-CH.sub.3                           2-C.sub.2 H.sub.53-CH.sub.3                                                                 2-Cyclopentyl-5-CH.sub.3                                                                    3-CH.sub.2 OH2-CH.sub.3                           2-C.sub.2 H.sub.54-CH.sub.3                                                                 3-Cyclopentyl-4-CH.sub.3                                                                    3-CH.sub.2 OH4-CH.sub.3                           2-C.sub.2 H.sub.55-CH.sub.3                                                                 3-Cyclopentyl-5-CH.sub.3                                                                    3-CH.sub.2 OH5-CH.sub.3                           3-C.sub.2 H.sub.52-CH.sub.3                                                                 4-Cyclopentyl-2-CH.sub.3                                                                    3-CH.sub.2 OH6-CH.sub.3                           3-C.sub.2 H.sub.55-CH.sub.3                                                                 4-Cyclopentyl-3-CH.sub.3                                                                    4-CH.sub.2 OH2-CH.sub.3                           4-C.sub.2 H.sub.52-CH.sub.3                                                                 2-(1-Cyclopenten-1-yl)                                                                      4-CH.sub.2 OH3-CH.sub.3                           4-C.sub.2 H.sub.53-CH.sub.3                                                                 3-(1-Cyclopenten-1-yl)                                                                      2-CH.sub.2 OH3-C.sub.2 H.sub.5                    2,3,4-triCH.sub.3                                                                           4-(1-Cyclopenten-1-yl)                                                                      2-CH.sub.2 OH4-C.sub.2 H.sub.5                    2,3,5-triCH.sub.3                                                                           2-(1-Cyclohexen-1-yl)                                                                       2-CH.sub.2 OH5-C.sub.2 H.sub.5                    2,4,5-triCH.sub.3                                                                           3-(1-Cyclohexen-1-yl)                                                                       3-CH.sub.2 OH2-C.sub.2 H.sub.5                    3,4,5-triCH.sub.3                                                                           4-(1-Cyclohexen-1-yl)                                                                       3-CH.sub.2 OH4-C.sub.2 H.sub.5                    2-CH.sub.2 CHCH.sub.2                                                                       2-CH.sub.2 CCH                                                                              3-CH.sub.2 OH5-C.sub.2 H.sub.5                    3-CH.sub.2 CHCH.sub.2                                                                       3-CH.sub.2 CCH                                                                              3-CH.sub.2 OH6-C.sub.2 H.sub.5                    4-CH.sub.2 CHCH.sub.2                                                                       4-CH.sub.2 CCH                                                                              4-CB.sub.2 OH2-C.sub.2 H.sub.5                    2-CH.sub.2 CH.sub.2 CHCH.sub.2 3-CH.sub.2 CH.sub.2 CHCH.sub.2 4-CH.sub.2      CH.sub.2 CHCH.sub.2 2-CH.sub.2 C(CH.sub.3)CH.sub.2                                           ##STR18##    4-CH.sub.2 OH3-C.sub.2 H.sub.5 2-CH.sub.2                                     OH3,4-diCH.sub.3 2-CH.sub.2 OH3,5-diCH.sub.3                                  2-CH.sub.2 OH4,5-diCH.sub.3                       3-CH.sub.2 C(CH.sub.3)CH.sub.2 4-CH.sub.2 C(CH.sub.3)CH.sub.2 2-Cyclopropy                   ##STR19##    3-CH.sub.2 OH2,4-diCH.sub.3 3-CH.sub.2                                        OH2,5-diCH.sub.3 3-CH.sub.2 OH4,5-diCH.sub.3      3-Cyclopropyl  4-Cyclopropyl 2-Cyclobutyl                                                    ##STR20##    3-CH.sub.2 OH4,6-diCH.sub.3 3-CH.sub.2                                        OH5,6-diCH.sub.3 4-CH.sub.2 OH2,3-diCH.sub.3      4-CH.sub.2 OH2,5-diCH.sub.3                                                                 2-CH.sub.2 CH(OH)CH.sub.34-CH.sub.3                             4-CH.sub.2 OH3,6-diCH.sub.3 3-CH.sub.2 OH4,5,6-triCH.sub.3                                  2-C(CH.sub.3).sub.2 OH4-CH.sub.3 3-C(CH.sub.3).sub.2                          OH6-CH.sub.3                                                                                 ##STR21##                                        2-CH.sub.2 CH.sub.2 OH 3-CH.sub.2 CH.sub.2 OH                                               4-C(CH.sub.3).sub.2 OH3-CH.sub.3 2-CH(CH.sub.3)OH4-C.sub.2                    H.sub.5                                                                                      ##STR22##                                        4-CH.sub.2 CH.sub.2 OH                                                                      2-CH.sub.2 CH.sub.2 OH5-C.sub.2 H.sub.5                                                     2,3-di-CH.sub.2 OH                                2-CH.sub.2 CH.sub.2 OH4-CH.sub.3                                                            3-CH(CH.sub.3)OH2,5-diCH.sub.3                                                              2,5-di-CH.sub.2 OH                                2-CH.sub.2 CH.sub.2 OH3-CH.sub.3                                                            4-CH.sub.2 CH.sub.2 OH3,5-diCH.sub.3                                                        2,4-di-CH.sub.2 OH                                2-CH.sub.2 CH.sub.2 OH5-CH.sub.3                                                            2-CH(C.sub.3 H.sub.7)OH                                                                     3,4-di-CH.sub.2 OH                                3-CH.sub.2 CH.sub.2 OH2-CH.sub.3                                                            3-CH(C.sub.3 H.sub.7)OH                                                                     3,5-di-CH.sub.2 OH                                3-CH.sub.2 CH.sub.2 OH4-CH.sub.3                                                            4-CH(C.sub.3 H.sub.7)OH                                                                     2-CH.sub.2 OH3-OH                                 3-CH.sub.2 CH.sub.2 OH5-CH.sub.3                                                            2-CH(C.sub.2 H.sub.5)CH.sub.2 OH                                                            2-CH.sub.2 OH3-OH6-CH.sub.3                       3-CH.sub.2 CH.sub.2 OH6-CH.sub.3                                                            3-CH(C.sub.2 H.sub.5)CH.sub.2 OH                                                            2-CH(CH.sub.2 OH).sub.2                           4-CH.sub.2 CH.sub.2 OH3-CH.sub.3                                                            4-CH(C.sub.2 H.sub.5)CH.sub.2 OH                                                            3-CH(CH.sub.2 OH).sub.2                           4-CH.sub.2 CH.sub.2 OH2-CH.sub.3                                                            2-CH.sub.2 (CH.sub.2).sub.3 OH                                                              4-CH(CH.sub.2 OH).sub.2                           2-CH(CH.sub.3)OH3-CH.sub.3                                                                  3-CH.sub.2 (CH.sub.2).sub.3 OH                                                              3-C(CH.sub.2 OH).sub.2                            2-CH(CH.sub.3)OH4-CH.sub.3                                                                  4-CH.sub.2 (CH.sub.2).sub.3 OH                                                              4-C(CH.sub.2 OH).sub.2                            2-CH(CH.sub.3)OH5-CH.sub.3                                                                  2-CH(CH.sub.3)CH.sub.2 CH.sub.2 OH                                                          2-CHOHCH.sub.2 OH                                 3-CH(CH.sub.3)OH2-CH.sub.3                                                                  3-CH(CH.sub.3)CH.sub.2 CH.sub.2 OH                                                          3-CHOHCH.sub.2 OH                                 3-CH(CH.sub.3)OH4-CH.sub.3                                                                  4-CH(CH.sub.3)CH.sub.2 CH.sub.2 OH                                                          4-CHOHCH.sub.2 OH                                 3-CH(CH.sub.3)OH5-CH.sub.3 3-CH(CH.sub.3)OH6-CH.sub.3                                        ##STR23##    2-COCH.sub.2 OH 3-COCH.sub.2 OH                   4-CH(CH.sub.3 )OH2-CH.sub.3 4-CH(CH.sub.3)OH3-CH.sub.3 2-CH(C.sub.2           H.sub.5)OH                                                                                   ##STR24##                                                                                   ##STR25##                                        3-CH(C.sub.2 H.sub.5)OH 4-CH(C.sub.2 H.sub.5)OH                                              ##STR26##    3-CH.sub.2 COCH.sub.3 2-CH.sub.2 COCH.sub.3       2-CH(CH.sub.3)CH.sub.2 OH                                                                   2-CH.sub.2 C(CH.sub.3).sub.2 OH                                                             4-CH.sub.2 COCH.sub.3                             3-CH(CH.sub.3)CH.sub.2 OH 4-CH(CH.sub.3)CH.sub.2 OH 4-CH(CH.sub.3)CH.sub.2     OH5-CH.sub.3 3-CH.sub.2 C(CH.sub.3).sub.2 OH 4-CH.sub.2 C(CH.sub.3).sub.2                   OH 4-C(CH.sub.2)CH.sub.2 OH                                                                 ##STR27##                                        2-(CH.sub.2).sub.3 OH 3-(CH.sub.2).sub.3 OH                                                 3-C(CH.sub.2)CH.sub.2 OH 2-C(CH.sub.2)CH.sub.2 OH                                            ##STR28##                                        4-(CH.sub.2).sub.3 OH 2-CH.sub.2 CH(OH)CH.sub.3                                             4-CH(OH)CHCH.sub.2 2-CH(OH)CHCH.sub.2                                                        ##STR29##                                        3-CH.sub.2 CH(OH)CH.sub.3 4-CH.sub.2 CH(OH)CH.sub.3                                         3-CH(OH)CHCH.sub.2 2-CH(OH)CH.sub.2 CHCH.sub.2                                               ##STR30##                                         ##STR31##    2-OCH.sub.3 3-OCH.sub.3                                                                     2-butoxy 3-butoxy                                  ##STR32##    2-OCH.sub.33-CH.sub.3 2-OCH.sub.34-CH.sub.3 2-OCH.sub.35-CH.                  sub.3         4-butoxy 4-butoxy-2-CH.sub.3 2-Isobutoxy           ##STR33##    3-OCH.sub.32-CH.sub.3 3-OCH.sub.34-CH.sub.3 3-OCH.sub.35-CH.                  sub.3         3-Isobutoxy 4-Isobutoxy 2-tert butoxy              ##STR34##    3-OCH.sub.36-CH.sub. 3 4-OCH.sub.32-CH.sub.3                                                3-tert butoxy 4-tert butoxy                        ##STR35##    4-OCH.sub.33-CH.sub.3 2-OC.sub.2 H.sub.5 3-OC.sub.2                                         2-OCH.sub.2CHCH.sub.2 3-OCH.sub.2CHCH.sub.2                                   4-OCH.sub.2CHCH.sub.2                              ##STR36##    4-OC.sub.2 H.sub.5 2-OC.sub.2 H.sub.53-CH.sub.3 2-OC.sub.2                    H.sub.54-CH.sub.3 2-OC.sub.2 H.sub.55-CH.sub.3                                              2-OCH.sub.2 CH.sub.2 OH 3-OCH.sub.2 CH.sub.2                                  OH 4-OCH.sub.2 CH.sub.2 OH 2-CH.sub.2OCH.sub.3     ##STR37##    3-OC.sub.2 H.sub.52-CH.sub.3 3-OC.sub.2 H.sub.54-CH.sub.3                                   3-CH.sub.2OCH.sub.3 3-CH.sub.2 OCH.sub.32CH.su                                b.3                                                ##STR38##    3-OC.sub.2 H.sub.55-CH.sub.3 3-OC.sub.2 H.sub.56-CH.sub.3                                    2-CH.sub.2 OC.sub.2 H.sub.5 3-CH.sub.2                                       OC.sub.2 H.sub.5                                   ##STR39##    4-OC.sub.2 H.sub.52-CH.sub.3 4-OC.sub.2 H.sub.53-CH.sub.3                                   4-CH.sub.2 OC.sub.2 H.sub.5 2-CH.sub.2                                        OC.sub.3 H.sub.7                                   ##STR40##    2-OCH.sub.34-C.sub.2 H.sub.5 4-OCH.sub.32,5-diCH.sub.3                                      3-CH.sub.2 OC.sub.3 H.sub.7 4-CH.sub.2                                        OC.sub.3 H.sub.7                                                2-OCH(CH.sub.3).sub.2                                                                       2-CH.sub.2 OCH(CH.sub.3).sub.2                                  3-OCH(CH.sub.3).sub.2                                           4-CH.sub.2 CHO                                                                              4-OCH(CH.sub.3).sub.2                                           3-CH.sub.2 CHO                                                                              4-OCH(CH.sub.3).sub.22-CH.sub.3                                 2-CH.sub.2 CHO                                                                 ##STR41##                                                                     ##STR42##                                                                     ##STR43##                                                                    3-CH.sub.2 OCH(CH.sub.3).sub.2                                                              3-OH2-CH.sub.3                                                                              3-SOCH.sub.3                                      4-CH.sub.2 OCH(CH.sub.3).sub.2                                                              3-OH4-CH.sub.3                                                                              4-SOCH.sub.3                                      2-CH.sub.2 OCH.sub.2 CHCH.sub.2                                                             3-OH5-CH.sub.3                                                                              2-SO.sub.2 CH.sub.3                               3-CH.sub.2 OCH.sub.2 CHCH.sub.2                                                             3-OH6-CH.sub.3                                                                              3-SO.sub.2 CH.sub.3                               4-CH.sub.2 OCH.sub.2 CHCH.sub.2                                                             3-OH2-C.sub.2 H.sub.55-CH.sub.3                                                             4-SO.sub.2 CH.sub.3                               2-CH.sub.2 CH.sub.2 OCHCH.sub.2                                                             3-OH5-C.sub.2 H.sub.52-CH.sub.3                                                             2-SC.sub.2 H.sub.5                                3-CH.sub.2 CH.sub.2 OCHCH.sub.2                                                             3-OH2-HC(CH.sub.3).sub.2                                                                    3-SC.sub.2 H.sub.5                                4-CH.sub.2 CH.sub.2 OCHCH.sub.2                                                             3-OH2-CH.sub.2 CH.sub.2 CH.sub.3                                                            4-SC.sub.2 H.sub.5                                2-CH.sub.2 CH.sub.2 OCH.sub.3                                                               3-OH2-butyl   2-SOC.sub.2 H.sub.5                               3-CH.sub.2 CH.sub.2 OCH.sub.3                                                               3-OH2-sec.butyl                                                                             3-SOC.sub.2 H.sub.5                               4-CH.sub.2 CH.sub.2 OCH.sub.3                                                               3-OH2-tert.butyl                                                                            4-SOC.sub.2 H.sub.5                               3-CH.sub.2 CH.sub.2 OCH.sub.34-CH.sub.3                                                     3-OH4-butyl   2-SO.sub.2 C.sub.2 H.sub.5                        2-CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                        3-OH5-sec.butyl                                                                             3-SO.sub.2 C.sub.2 H.sub.5                        3-CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                        3-OH2,4,5-tri-CH.sub.3                                                                      4-SO.sub.2 C.sub. 2 H.sub.5                       4-CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                        3-OH4,5,6-tri-CH.sub.3                                                                      2-CH.sub.2 SCH.sub.3                              2-CH(OCH.sub.3)CH.sub.3                                                                     3-OH6-CHCH(CH.sub.3)                                                                        3-CH.sub.2 SCH.sub.3                              3-CH(OCH.sub.3)CH.sub.3                                                                     3-OH2-CHCH(CH.sub.3)                                                                        2-CH.sub.2 SOCH.sub.3                             4-CH(OCH.sub.3)CH.sub.3                                                                     3-OH4-CH.sub.2 CHCH.sub.2                                                                   4-CH.sub.2 SOCH.sub.3                             2-CH(OC.sub.2 H.sub.5)CH.sub.3                                                              3-OH2-Cl      2-CH.sub.2 SO.sub.2 CH.sub.3                      3-CH(OC.sub.2 H.sub.5)CH.sub.3                                                              3-OH5-Cl      4-CH.sub.2 SO.sub.2 CH.sub.3                      4-CH(OC.sub.2 H.sub.5)CH.sub.3                                                              3-OH6-Cl      2-CH.sub.2 SC.sub.2 H.sub.5                       2-(CH.sub.2).sub.3 OCH.sub.3                                                                3-OH2-Br      3-CH.sub.2 SC.sub.2 H.sub.5                       3-(CH.sub.2).sub.3 OCH.sub.3                                                                2-CH.sub.2 OCH.sub.2 CH.sub.2 OH                                                            4-CH.sub.2 SC.sub.2 H.sub.5                       4-(CH.sub.2).sub.3 OCH.sub.3                                                                3-CH.sub.2 OCH.sub.2 CH.sub.2 OH                                                            2-CH.sub.2 SOC.sub.2 H.sub.5                       ##STR44##    4-CH.sub.2 OCH.sub.2 CH.sub.2 OH 2-(CH.sub.2).sub.2                           OCH.sub.2 CH.sub.2 OH                                                                       3-CH.sub.2 SOC.sub.2 H.sub.5 4-CH.sub.2                                       SOC.sub.2 H.sub.5                                  ##STR45##    3-(CH.sub.2).sub.2 OCH.sub.2 CH.sub.2 OH 4-(CH.sub.2).sub.2                   OCH.sub.2 CH.sub.2 OH                                                                       2-CH.sub.2 SO.sub.2 C.sub.2 H.sub.5 3-CH.sub.2                                 SO.sub.2 C.sub.2 H.sub.5                          ##STR46##    2-OH 2-OH3-CH.sub.3                                                                         4-CH.sub.2 SO.sub.2 C.sub.2 H.sub.5 4-SCH.sub.                                2 CH.sub.2 CH.sub.3                               3-OH2-C.sub.2 H.sub.5                                                                       2-OH4-CH.sub.3                                                                              3-SOCH.sub.2 CH.sub.2 CH.sub.3                    3-OH4-C.sub.2 H.sub.5                                                                       2-OH5-CH.sub.3                                                                              2-SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.3             3-OH5-C.sub.2 H.sub.5                                                                       4-OH          2-SCH(CH.sub.3).sub.2                             3-OH6-C.sub.2 H.sub.5                                                                       4-OH2-CH.sub.3                                                                              3-SOCH(CH.sub.3).sub.2                            3-OH2,4-di-CH.sub.3                                                                         4-OH3-CH.sub.3                                                                              4-SO.sub.2 CH(CH.sub.3).sub.2                     3-OH2,5-diCH.sub.3                                                                          3-SCH.sub.3   2-CH.sub.2 CH.sub.2 SCH.sub.3                     3-OH4,5-diCH.sub.3                                                                          4-SCH.sub.3   3-CH.sub.2 CH.sub.2 SOCH.sub.3                    3-OH4,6-diCH.sub.3                                                                          2-SOCH.sub.3  4-CH.sub.2 CH.sub.2 SO.sub.2 CH.sub.3             2-CH.sub.2 CH.sub.2 SOC.sub.2 H.sub.5                                                       2-CF.sub.3    6-CH.sub.2 OCH.sub.33-Br                          3-CH.sub.2 CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                                                3-CF.sub. 3   2-CH.sub.2 OCH.sub.33-Cl                          4-CH.sub.2 CH.sub.2 SC.sub.2 H.sub.5                                                        4-CF.sub.3    4-CH.sub.2 OCH.sub.33-Cl                          2-SCH.sub.2 CH.sub.2 OH                                                                     3-J           5-CH.sub.2 OCH.sub.33-Cl                          3-SCH.sub.2 CH.sub.2 OH                                                                     2-OCH.sub.33-Br                                                                             6-CH.sub.2 OCH.sub.33-Cl                          4-SCH.sub.2 CH.sub.2 OH                                                                     4-OCH.sub.33-Br                                                                             2-CH.sub.2 OCH.sub.33-F                           2-SOCH.sub.2 CH.sub.2 OH                                                                    5-OCH.sub.33-Br                                                                             4-CH.sub.2 OCH.sub.33-F                           3-SOCH.sub.2 CH.sub.2 OH                                                                    6-OCH.sub.33-Br                                                                             5-CH.sub.2 OCH.sub.33-F                           4-SOCH.sub.2 CH.sub.2 OH                                                                    2-OCH.sub.33-Cl                                                                             6-CH.sub.2 OCH.sub.33-F                           2-SO.sub.2 CH.sub.2 CH.sub.2 OH                                                             4-OCH.sub.33-Cl                                                 3-SO.sub.2 CH.sub.2 CH.sub.2 OH                                                             5-OCH.sub.33-Cl                                                 4-SO.sub.2 CH.sub.2 CH.sub.2 OH                                                             6-OCH.sub.33-Cl                                                 2-SCH.sub.2CHCH.sub.2                                                                       2-OCH.sub.33-F                                                  3-SOCH.sub.2 CHCH.sub.2                                                                     4-OCH.sub.33-F                                                  4-SO.sub.2 CH.sub.2 CHCH.sub.2                                                              5-OCH.sub.33-F                                                  2-SCHCHCH.sub.3                                                                             6-OCH.sub.33-F                                                  3-SCHCHCH.sub.3                                                                             3-F5-OH                                                         4-SCHCHCH.sub.3                                                                             3-Cl5-OH                                                        4-CH.sub.2 SCH.sub.2 CHCH.sub.2                                                             3-Br5-OH                                                                      3-J5-OH                                                                       2-CH.sub.2 OH3-Br                                                             4-CH.sub.2 OH3-Br                                                             5-CH.sub. 2 OH3-Br                                                            6-CH.sub.2 OH3-Br                                                             2-CH.sub.2 OH3-Cl                                                             4-CH.sub.2 OH3-Cl                                                             5-CH.sub.2 OH3-Cl                                                             6-CH.sub.2 OH3-Cl                                                             2-CH.sub.2 OH3-F                                                              4-CH.sub.2 OH3-F                                                              5-CH.sub.2 OH3-F                                                              6-CH.sub.2 OH3-F                                                              5-OC.sub.2 H.sub.53-Br                                                        5-OC.sub.2 H.sub.53-Cl                                                        5-OC.sub.2 H.sub.53-F                                                         2-CH.sub.2 OCH.sub.33-Br                                                      4-CH.sub.2 OCH.sub.33-Br                                                      5-CH.sub.2 OCH.sub.33-Br                                        __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________     ##STR47##                                                                                      ##STR48##                                                                                        ##STR49##                                R = H            R = H              R = H                                       = 7-OH           = 8-CH.sub.3         4-OH                                    = 7-OCH.sub.3    = 8-OH               4-OCH.sub.3                             = 7-CH.sub.2 OH  = 8-OH, 3-CH.sub.3   1-Cl                                    = 7,7-diCH.sub.2 OH                                                                            = 8-CH.sub.2 OH      5-Cl                                    = 7-Cl           = 8-CH.sub.2 OH, 3-CH.sub.3                                = 7-exo-methylene = 7-CONH.sub.2 = 3-OH                                                          = 8-OCH.sub.3 = 8,8-di-CH.sub.2 OH = 8-Cl                                                       ##STR50##                                = 3-CH.sub.2 OH    = 8-Br           R = H                                     = 4-CH.sub.3       = 8-exo-methylene  = 4-OH                                  = 3-CH.sub.3                                                                  = 4-CH.sub.2 OH    = 8-CONH.sub.2     = 4-OCH.sub.3                           = 5-OH, 7-CH.sub.3 = 8-Oxo            = 2-Cl                                  = 6-OH, 7-CH.sub.3 = 6-Cl             = 5-Cl                                  = 5-CH.sub.3       = 5-OH                                                     = 6-CH.sub.3 = 7-CH.sub.3                                                                        = 5-oxo = 5-Cl = 3-CH.sub.2 OH                                                                  ##STR51##                                 ##STR52##         = 3-OH = 4-OCH.sub.3 = 2-CH.sub.3                           ##STR53##         = 3-CH.sub.3 = 4-CH.sub.3                                                    ##STR54##                                                                     ##STR55##                                                                     ##STR56##                                                    ##STR57##                                                                                      ##STR58##                                                                                        ##STR59##                                 ##STR60##                                                                                      ##STR61##                                                                                        ##STR62##                                 ##STR63##                                                                                      ##STR64##                                                                                        ##STR65##                                 ##STR66##                                                                                      ##STR67##                                                                                        ##STR68##                                 ##STR69##                                                                                      ##STR70##                                                                                        ##STR71##                                 ##STR72##                                                                                      ##STR73##                                                    ##STR74##                                                                                      ##STR75##                                                   __________________________________________________________________________

The illustrative examples below of syn compounds which can be preparedaccording to the invention serve to illustrate the invention in moredetail but do not restrict it to these.

EXAMPLE 1 (a) Trifluoroacetate of(6R,7R)-3-acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-carboxymethyloxyimino-acetamido]-ceph-3-em-4-carboxylicacid

A solution of 1.7 g (2 mmoles) oftert.-butyl(6R,7R)-3-acetoxymethyl-7-[(Z)-2-tert.-butoxycarbonylmethyloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-ceph-3-em-4-carboxylatein 20 ml of trifluoroacetic acid was stirred for 30 minutes at roomtemperature. The solution was concentrated, and the residue was taken upin ether/n-pentane (2:1), filtered off with suction, washed with thesame solvent mixture, and dried in air. The yield is quantitative. IR(KBr): 1800 cm⁻¹ (lactam-CO).

(b) Monopotassium salt of(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxymethyloxyimino)-acetamido]-3-[(2,3-cyclopenteno-1-pyridinium)methyl]-ceph-3em-4-carboxylateProcess (a)

1.2 g (2 mmoles) of the product of stage (a) were suspended in 4 ml ofwater and dissolved by adding 0.6 g of potassium hydrogen carbonate. 3.9g (40 mmoles) of potassium thiocyanate and 0.71 ml (6 mmoles) of2,3-cyclopentenopyridine were then added, and the pH of the mixture wasadjusted to 6.6 by means of 85% strength phosphoric acid. The mixturewas heated for 3 hours at 65°-70° C. The mixture was diluted with 32 mlof acetone, a small amount of undissolved material was filtered off, andthe filtrate was chromatographed over 200 g of silica gel (Merck0.063-0.2 mm). The neutral salts were eluted with acetone/water (8:1),and the product was eluted with acetone/water (2:1). The freeze-driedcrude product was re-chromatographed over silica gel (Merck, Lobar Bcolumn, Article No. 10,401, about 1 bar, acetone/water 2:1).Freeze-drying of the product fractions (fractions 7-10, 60 ml) produced0.25 g (21% of theory) of the title compound in the form of a colorlesssolid.

IR (KBr): 1770 cm⁻¹ (lactam-CO).

¹ H-NMR (CF₃ CO₂ D): δ=2.3-2.8 (m, 2H, cyclopentene-H); 3.1-4.0 (m, 6H,4 cyclopentene-H and SCH₂); 5.09 (s, 2H, OCH₂); 5.1-6.25 (m, 4H, CH₂ Pyand 2 lactam-H); 7.43 (s, 1H, thiazole); 7.65-8.65 ppm (m, 3H, Py).

EXAMPLE 2 Monosodium salt of(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxymethyloxyimino)-acetamido]-3-[(4-cyclopropyl-1-pyridinium)methyl]-ceph-3-em-4-carboxylateProcess (b)

0.45 g (2.2 mmoles) of dicyclohexylcarbodiimide was added to a solutionof 1.1 g (2 mmoles) of(Z)-2-(2-tert.-butoxycarbonylmethyloxyimino)-2-(2-tritylaminothiazol-4-yl)-aceticacid and 0.31 g (2 mmoles) of 1-hydroxy-1H-benzotriazole hydrate in 15ml of N,N-dimethylformamide. After stirring for 2 hours at roomtemperature, the mixture was cooled down to -20° C., and a solution of0.8 g (2 mmoles) of 7-amino-3-[(4-cyclopropyl-1-pyridiniummethyl]-ceph-3-em-4-carboxylatedihydrochloride and 0.6 g (5 mmoles) of N,N-dimethylaniline in 5 ml ofN,N-dimethylformamide was added. The mixture was stirred for 2 hours andleft to stand overnight at room temperature. The precipitate(dicyclohexylurea) was filtered off, and the filtrate was added dropwisewith stirring to 200 ml of diethyl ether. The solids were filtered off,washed with ether and dried. The solid material was dissolved in 10 mlof trifluoroacetic acid. The solution was concentrated after 30 minutes,and the residue was taken up in either/n-pentane (2:1). The solids wasfiltered off, and washed with ether and dried. The solid material wassuspended in 4 ml of water and dissolved by adding sodium bicarbonate.The solution was chromatographed over silica gel (Merck, Lobar C columnArticle No. 10,402, about 1 bar, acetone/water 2:1). The productfractions (fractions 26-36, 180 ml) were concentrated and freeze-dried.Yield: 0.23 g (20% of theory) of a colorless solid.

IR (KBr) 1770 cm⁻¹ (lactam-CO).

¹ H-NMR (CF₃ CO₂ D): δ=1.05-2.6 (m, 5H, cyclopropyl); 3.40 and 3.82 (AB,J=18 Hz, 2H, SCH₂); 5.06 (s, 2H, OCH₂); 5.1-6.25 (m, 4H, CH₂ Py and 2lactam-H); 7.42 (s, 1H, thiazole); 7.63 and 8.65 ppm (AA'BB', 4H, Py).

EXAMPLE 3 (a)(Z)-2-(2-tert.-butoxycarbonyl-2-propen-1-yloxyimino)-2-(2-tritylaminothiazol-4-yl)-aceticacid

1.5 ml of water were added to a mixture of 9.6 g (85.6 mmoles) ofpotassium tert.-butylate and 17.2 g (40 mmoles) of(Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid in 500 mlof tetrahydrofuran. An almost clear blue-colored solution was obtainedafter 30 minutes' stirring. 10.2 g (46 mmoles) of tert.-butyl2-(bromomethyl)-acrylate (R. Lattrell and G. Lohaus, Liebigs Annalen derChemie, 1974, 870) were added, and the color of the solution changedfrom blue to red-brown within 10 minutes. The solution was concentratedat room temperature after stirring for 2 hours, and the residue wasdissolved in 400 ml of ethyl acetate/water (1:1).

The aqueous phase was adjusted to pH 2 by means of 1N hydrochloric acidand extracted 3× with ethyl acetate. The combined organic phases weredried with sodium sulfate, and filtered, the filtrate was concentrated,and the residue was triturated with n-pentane.

The undissolved red-brown product was filtered off with suction anddried in air. Yield: 17.2 g (76% of theory).

(b) Monosodium salt of(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-(2-carboxy-2-propen-1-yloxyimino)-acetamido]-3-[(2,3-cyclopenteno-1-pyridinium)methyl]-ceph-3-em-4-carboxylateProcess (b)

A mixture of 4 ml of a 2 molar solution of phosgene in toluene (8mmoles) and 2.0 ml of N,N-dimethylacetamide was added at -20° C. to asolution of 4 g (7 mmoles) of the product of stage (a) and 0.95 ml (7.1mmoles) of triethylamine in 5 ml of N,N-dimethylacetamide. The mixturewas stirred for 1 hour at -10° C., and this solution was then stirredinto a cooled suspension at -60° C. of 3.3 g (8 mmoles) of7-amino-3-[(2,3-cyclopenteno-1-pyridinium)methyl]-ceph-3-em-4-carboxylatedihydrochloride and 3 ml (22 mmoles) of triethylamine in 20 ml ofmethylene chloride. The mixture was stirred for 1 hour at -20° C. Thephases were separated after 20 ml of water had been added, and theaqueous phase was extracted two more times with methylene chloride. Theorganic phase was dried with sodium sulfate and filtered, and thesolvent was removed in vacuo. The residue was dissolved in 30 ml oftrifluoroacetic acid, and the solution was stirred for 30 minutes atroom temperature. It was concentrated, triturated with ether/n-pentane(2:1), filtered with suction, and the solids retained were dried. Thecrude product was dissolved in 5 ml of water with the addition of sodiumbicarbonate and and chromatographed over silica gel (Merck, Lobar Ccolumn, about 1 bar, acetone/water 2:1). The product fractions(fractions 45-60, 250 ml) were concentrated and freeze-dried. 450 mg(11% of theory) of the title compound are obtained in the form of acolorless solid.

IR (KBr): 1775 cm⁻¹ (lactam-CO).

¹ H-NMR (CF₃ CO₂ D): δ=2.3-2.8 (m, 2H, cyclopentene-H); 3.13-4.0 (m, 6H,4 cyclopentene-H and SCH₂); 5.1-6.4 (m, 6H, N--O--CH₂ to 5.20, CH₂ Pyand 2 lactam-H); 6.6-6.95 (m, 2H, C═CH₂); 7.42 (s, 1H, thiazole);7.65-8.66 ppm (m, 3H, Py).

The compounds listed below, and which correspond to the general formulaI with l=0 and R¹ =hydrogen, were obtained analogously to Example 1, 2and 3.

                                      TABLE 3                                     __________________________________________________________________________     ##STR76##                                                                                                     Process                                                                       Yield as %                                   Example                                                                            (CH.sub.2).sub.n (A).sub.m R.sup.2                                                           B            of theory                                                                           .sup.1 HNMR: δ (ppm) in                                                 CF.sub.3 CO.sub.2 D                    __________________________________________________________________________    4    CH.sub.2 CO.sub.2 K                                                                           ##STR77##   a(18) 2.1-2.8(m, cyclopentene-H);                                                   3.0-4.0(m, 6H, 4 cyclopentene-H                                               and SCH.sub.2); 4.95-6.4(m, 6H,                                               OCH.sub.2 to 5.06, CH.sub.2 Py and                                            2 lactam-H); 7.42(s,                                                          1H, thiazole); 7.77-8.9(m, 3H,                                                Py)                                    5    CH.sub.2 CO.sub.2 K                                                                           ##STR78##   a(21) 1.83-2.42(m, 4 cyclohexene-H);                                                2.9-3.4(m, cyclo- hexene-H); 3.40                                             amd 3,73(AB, J=18Hz, 2H,                                                      SCH.sub.2); 5.06(s, 2H,                                                       OCH.sub.2); 5.2-6.2(m, 4H,                                                    CH.sub.2 Py and 2 lactam-H);                                                  7.42(s, 1H, thiazole); 7.6-8.75(m,                                            3H, Py)                                6    CH.sub.2 CO.sub.2 K                                                                           ##STR79##   a(22) 1.8-2.65(m, 4 cyclohenene-h);                                                 2.8-3.35 (m, 4 cyclohexene-H);                                                3.40 and 3.82(AB, J= 18Hz, 2H,                                                SCH.sub.2); 5.05(s, 2H,                                                       OCH.sub.2); 5.15- 6.3(m, 4H,                                                  CH.sub.2 Py and 2 lactam-H);                                                  7.43(s, 1H, thiazole); 7.6-8.7(m,                                             3H, Py)                                7    CH.sub.2 CO.sub.2 K                                                                           ##STR80##   a(24) 1.9-2.5(m, 2 pyran-H); 2.8-3.5(m,                                             2 pyran-H); 3.41 and 3.81(AB,                                                 J=19Hz), 2H, SCH.sub.2);                                                      4.45-4.85(m, 2 pyran-H);                                                      4.9-6.35(m, 6H, OCH.sub.2 to 5.08,                                            CH.sub.2 Py and 2 lactam-H);                                                  7.15-7.5(m, 2H, thiazole-H to 7.42                                            and PyH); 8.3-8.7(m, 2H, Py)           8    CH.sub.2 CO.sub.2 K                                                                           ##STR81##   a(26) 1.55-2.25(m, 6H, cycloheptene-H);                                             3.03-3.7 (m, 6H, SCH.sub.2 and 4                                              cycloheptene-H); 5.08(s, 2H,                                                  OCH.sub.2); 5.1-6.36(m, 4H,                                                   CH.sub.2 Py and 2 lactam-H);                                                  7.43(s, 1H, thiazole); 7.55-8.75                                              (m, 2H, Py)                            9    CH.sub.2 CO.sub.2 K                                                                           ##STR82##   a(26) 2.15-3.85(m, 6H, 4 cyclopentene-H,                                            SCH.sub.2) 4.95-6.35(m, 7H,                                                   OCH.sub.2 to 5.05, 1 cyclo-                                                   pentene-H, CH.sub.2 Py and 2                                                  lactam-H); 7.41(s, 1H, thiazole);                                             7.8-8.95(m, 3H, Py)                    10   C(CH.sub.3).sub.2 CO.sub.2 K                                                                  ##STR83##   a(24) 1.79(s, 6H, 2 × CH.sub.3);                                              2.3-2.85(m, 2 cyclopentene- H);                                               3.1-3.9(m, 6H, 4 cyclopentene-H                                               and SCH.sub.2); 5.25-6.25(m, 4H,                                              CH.sub.2 Py and 2 lactam-H);                                                  7.40(s, 1H, thiazole); 7.6-8.7(m,                                             3H, Py)                                11   C(CH.sub.3).sub.2 CO.sub.2 K                                                                  ##STR84##   a(26) 1.80(s, 6H, 2 × CH.sub.3);                                              2.25-2.7(m, 2 cyclopentene- H);                                               3.05-4.05(m, 6H, 4 cyclopentene-H                                             and SCH.sub.2); 5.15-6.35(m, 4H,                                              CH.sub.2 Py and 2 lactam-H);                                                  7.41(s, 1H, thiazole);                                                        7.63-8.85(m, 3H, Py)                   12   C(CH.sub.3).sub.2 CO.sub.2 K                                                                  ##STR85##   a(19) 1.65-2.4(m, 10H, 4 cyclohexene-H                                              and 2 × CH.sub.3 to 1.79);                                              2.95-4.05(m, 6H, 4 cyclohexene-H                                              and SCH.sub.2); 5.25-6.25(m, 4H,                                              CH.sub.2 Py and 2 lactam-H);                                                  7.40(s, 1H, thiazole); 7.6-8.65(m,                                            3H, Py)                                13   C(CH.sub.3).sub.2 CO.sub.2 K                                                                  ##STR86##   a(21) 1.65-2.35(m, 10H, 4 cyclohexene-H                                             and 2 × CH.sub.3 to 1.80);                                              2.8-3.4(m, 4 cyclohexene-H); 3.43                                             and 3.83(AB, J=18Hz, 2H,                                                      SCH.sub.2); 5.15-6.36(m, 4H,                                                  CH.sub. 2 Py and 2 lactam-H);                                                 7.40(s, 1H, thiazole); 7.6-8.8(m,                                             3H, PY)                                14   C(CH.sub.3).sub.2 CO.sub.2 K                                                                  ##STR87##   a(18) 1.80(s, 6H, 2 × CH.sub.3);                                              1.9-2.5(m, 2 pyran-H); 2.83-3.16(m,                                            2 pyran-H); 3.42 and 3.79(AB,                                                J=19Hz, 2H, SCH.sub.2);                                                       4.45-4.75(m, 2-pyran-H);                                                      4.95-6.25(m, 4H, CH.sub.2 Py and 2                                            lactam-H); 7.15-7.45(m, 2H,                                                   thiazole-H to 7.40 and PyH)                                                   8.3-8.65(m, 2H, Py)                    15   C(CH.sub.3).sub.2 CO.sub.2 K                                                                  ##STR88##   a(21) 1.65-2.35(m, 10H, 4 cyclohexene-H                                             and s of (CH.sub.3).sub.2 to                                                  1.80); 2.54(s, 3H, CH.sub.3);                                                 2.8-3.75(m, 6H, 4 cyclo- hexene-H                                             and SCH.sub.2); 5.2-6.28(m, 4H,                                               CH.sub.2 Py and 2 lactam-H);                                                  7.41(s, 1H, thiazole); 8.11 and                                               8.41 (1H, bs, Py each)                 16                                                                                  ##STR89##                                                                                    ##STR90##   a(26)                                                                                ##STR91##                             17   CH.sub.2 CO.sub.2 CH.sub.3                                                                    ##STR92##   a(16) 2.35-2.9(m, 2 cyclopentene-H);                                                3.1-3.85 (m, 6H, 4 cyclopentene--H                                            and SCH.sub.2); 3.96 (s, 3H,                                                  CH.sub.3); 5.02(s, 2H, OCH.sub.2);                                            5.16- 6.4(m, 4H, CH.sub.2 Py and 2                                            lactam-H); 7.41 (s, 1H, thiazole);                                            7.6-8.7(m, 3H, Py)                     18   CH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                             ##STR93##   a(22)                                                                                ##STR94##                             19   CH.sub.2 CN                                                                                   ##STR95##   a(24) 2.17-2.83(m, 2H, cyclopentene-H);                                             2.95-3.85 (m, 6H, 4-cyclopentene-H                                            and SCH.sub.2); 5.02-6.21 (m, 6H,                                             OCH.sub.2s to 5.13, CH.sub.2 Py                                               and 2 lactam-H) 7.45(s, 1H,                                                   thiazole); 7.65-8.72(m, 3H, Py)        20   CH.sub.2 CONH.sub.2                                                                           ##STR96##   a(31) 2.18-2.81(m, 2H, cyclopentene-H);                                             3.05-3.95 (m, 6H, 4 cyclopentene-H                                            and SCH.sub.2); 4.92- 6.25(m, 6H,                                             OCH.sub.2, CH.sub.2 Py and 2                                                  lactam-H); 7.46(s, 1H, thiazole);                                             7.66-8.75(m, 3H, Py)                   21                                                                                  ##STR97##                                                                                    ##STR98##   a(16) 1.55-2.85(m, 6H, 4 cyclopropyl-H                                              and 2  cyclopentene-H);                                                       3.05-4.0(m, 6H, 4 cyclo- pentene-H                                            and SCH.sub.2); 5.15-6.25(m, 4H,                                              CH.sub.2 Py and 2 lactam-H);                                                  7.42(s, 1H, thiazole); 7.75-8.95(m,                                            3H, Py)                               22                                                                                  ##STR99##                                                                                    ##STR100##  a(22) 1.9-3.1(m, 8H, 2 cyclopentene-H 6                                             cyclobutyl-H); 3.1-3.9(m, 6H, 4                                               cyclopentene-H and SCH.sub.2);                                                5,45(d, J=5Hz, lactam-H); 5.48 and                                            5.96(AB, J=14Hz, 2H, CH.sub.2 Py);                                            6.15(d, J=5Hz, lactam-H); 7.42(s,                                             1H, thiazole); 7.63-8.72(m, 3H,                                               Py)                                    23                                                                                  ##STR101##                                                                                   ##STR102##  a(25) 1.4-2.8(m, 10H, 2 cyclopentene-H                                              and 8 cyclopentene-H); 3.1-3.9(m,                                             6H, 4-cyclo- pentene-H and                                                    SCH.sub.2); 4.95-6.25(m, 4H,                                                  CH.sub.2 Py and 2 lactam-H);                                                  7.42(s, 1H, thiazole); 7.63-8.82(m,                                            3H, Py)                               24                                                                                  ##STR103##                                                                                   ##STR104##  a(32) 2.17- 2.86(m, 2H, cyclopentene-H);                                            2.92- 3.98(m, 6H, 4-cyclopentene-H                                            and SCH.sub.2); 4.98-6.23(m, 6H,                                              OCH.sub.2s to 5.46, CH.sub.2 Py                                               and 2 lactam-H); 7.43(s, 1H,                                                  thiazole); 7.63-8.75(m, 7H, 4                                                 phenyl-H, 3 PyH)                       __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     ##STR105##                                                                                              Process                                                                       Yield as %                                         Example                                                                             (CH.sub.2).sub.n (A).sub.m R.sup.2                                                       Substituent                                                                             of theory                                                                            .sup.1 HNMR: δ (ppm) in CF.sub.3                                        CO.sub.2 D                                  __________________________________________________________________________    25    CH.sub.2 CO.sub.2 K                                                                      4-CH.sub.3                                                                              a (28) 2,77 (s, 3H, CH.sub.3); 3,42 and 3,82                                         (AB, J=19Hz,                                                                  2H, SCH.sub.2); 4.9-6.35 (m, 6H,                                              OCH.sub.2 to 5.08,                                                            CH.sub.2 Py and 2 lactam-H); 7,42 (s,                                         1H, thiazole);                                                                7.92 and 8.82 (AA'BB', J=6Hz, 4H, Py)       26    CH.sub.2 CO.sub.2 K                                                                      4-CH.sub.2 CH.sub.2 CH.sub.3                                                            a (24) 1.08 (t, J=7Hz, 3H, CH.sub.3); 1.5-2.15                                       (m, 2H,                                                                       CH.sub.2); 1.65-3.17 (m, 2H, CH.sub.2);                                       3.42 and 3.82                                                                 (AB, J=19Hz, 2H, SCH.sub.2); 1.85-6.35                                        (m, 6H, OCH.sub.2                                                             to 5.08, CH.sub.2 Py and 2 lactam-H);                                         7.42 (s, 1H,                                                                  thiazole); 7.93 and 8.83 (AA' BB',                                            J=6Hz; 4H,                                                                    Py)                                         27    CH.sub.2 CO.sub.2 K                                                                      3-CH.sub.2 OH                                                                           a (27) 3.48 and 3.87 (AB, J=19Hz, 2H,                                                SCH.sub.2); 5.08                                                               ##STR106##                                                                   1H, thiazole); 7.6-9.25 (m, 4H, Py)         28    CH.sub.2 CO.sub.2 K                                                                       ##STR107##                                                                             a (29) 1.64 (d, J=7Hz, CH.sub.3); 3.45 and                                           3.86 (AB,  J=19Hz, 2H, SCH.sub.2);                                            4.9-6.4 (m, 6H, OCH.sub.2 5.07,                                               CH.sub.2 Py and 2 lactam-H); 7.41 (s,                                         1H, thiazole); 8.22 and 8.98 (AA' BB',                                        J=7Hz, 4H, Py)                              29    CH.sub.2 CO.sub.2 K                                                                      4-OCH.sub.3                                                                             a (31) 3.43 and 3.82 (AB, J=19Hz, 2H,                                                SCH.sub.2); 4.22                                                              (s, 3H, OCH.sub.3); 5.08 (s, 2H,                                              OCH.sub.2); 5.2-6.25                                                          (m, 4H, CH.sub.2 Py and 2 lactam-H);                                          7.43 (s, 1H,                                                                  thiazole); 7.48 and 8.75 (AA' BB',                                            J=7Hz,                                                                        4H, Py)                                     30    CH.sub.2 CO.sub.2 K                                                                      3-C.sub.6 H.sub.5                                                                       a (18) 3.50 and 3.88 (AB, J=19Hz, 2H,                                                SCH.sub.2) 4.9-                                                               6.45 (m, 6H, OCH.sub.2 to 5.07,                                               CH.sub.2 Py and 2                                                             lactam-H); 7.42 (s, 1H, thiazole);                                            7.4-9.4                                                                       (m, 9H, 6 phenyl-H and 4 PyH)               31    CH.sub.2 CO.sub.2 K                                                                      3-Cl      a (22) 3.50 and 3.89 (AB, J=19Hz, 2H,                                                SCH.sub.2); 5.08 -    (s, 2H,                                                 OCH.sub.2); 5.1-6.45 (m, 4H, CH.sub.2                                         Py and                                                                        2 lactam-H); 7.43 (s, 1H, thiazole);                                          7.6-9.25                                                                      (m, 4H, Py)                                 32    CH.sub.2 CO.sub.2 K                                                                      4-CH.sub.2 CH.sub.2 SO.sub.3 K                                                          a (32) 3.4-4.0 (m, 6H, SCH.sub.2 and CH.sub.2                                        CH.sub.2); 4.9-6.3                                                            (m, 6H, OCH.sub.2 to 5.09, CH.sub.2 Py                                        and 2 lactam-H);                                                              7.42 (s, 1H, thiazole); 8.15 and 8.81                                         (AA' BB',                                                                     J=7Hz, 4H, Py)                              33    CH.sub.2 CO.sub.2 K                                                                      3-C.sub.2 H.sub.5                                                                       a (28)                                                                                ##STR108##                                                                   CH.sub.2 Py and 2 lactam-H); 7.42 (s,                                         1H, thiazole);                                                                 7.85-9.05 (m, 4H, Py)                      34    CH.sub.2 CO.sub.2 K                                                                      3-CH.sub.35-CH.sub.3                                                                    a (25) 2.65 (s, 6H, CH.sub.3 Py); 3.45 and                                           3.79 (AB, J=                                                                  19Hz, 2H, SCH.sub.2); 4.8-6.3 (m, 6H,                                         OCH.sub.2 to 5.08,                                                            CH.sub.2 Py and 2 lactam-H); 7.41 (s,                                         1H, thiazole);                                                                8.15-8.61 (m, 3H, Py)                       35    CH.sub.2 CO.sub.2 K                                                                      4-CH.sub.2 C.sub.6 H.sub.5                                                              a (15) 3.43 and 3.84 (AB, J=19Hz, 2H,                                                SCH.sub.2); 4.35                                                               ##STR109##                                                                   C.sub.6 H.sub.5 and thiazole); 7.95 and                                       8.81 (AA' BB', J=                                                             6Hz, 4H, Py)                                36    CH.sub.2 CO.sub.2 K                                                                      3-OH      a (28) 3.45 and 3.85 (AB, J=19Hz, 2H,                                                SCH.sub.2); 4.95-                                                             6.15 (m, 6H, OCH.sub. 2 to 5.07,                                              CH.sub.2 Py and 2 lactam-                                                     H); 7.41 (s, 1H, thiazole); 7.75-8.82                                         (m, 4H, Py)                                 37    CH.sub.2 CO.sub.2 K                                                                      3-CH.sub.2 CH.sub.2 CH.sub.2 OH                                                         a (24) 2.18 (m, 2H, propyl); 2.85-4.1 (m, 6H,                                        SCH.sub.2                                                                     and 4 propyl-H); 5.07 (s, 2H,                                                 OCH.sub.2); 5.1-6.48                                                          (m, 4H, CH.sub.2 Py and 2 lactam-H);                                          7.42 (s, 1H,                                                                  thiazole); 7.5-9.3 (m, 4H, Py)              38    CH.sub.2 CO.sub.2 K                                                                      4-CH.sub.2 OCH.sub.3                                                                    a (28) 3.46 and 3.80 (AB, J=19Hz, 2H,                                                SCH.sub.2); 3.72                                                               ##STR110##                                                                   (s, 1H, thiazole); 8.12 and 8.97                                              (AA'BB', J=6Hz, 4H, Py)                     39    CH.sub.2 CO.sub.2 K                                                                      3-CH.sub.2 CHCH.sub.2                                                                   a (27)                                                                                ##STR111##                                 40    CH.sub.2 CO.sub.2 K                                                                      3-COC.sub.6 H.sub.5                                                                     a (14) 3.43 and 3.83 (AB, J=19Hz, 2H,                                                SCH.sub.2); 4.94-                                                             6.21 (m, 6H, OCH.sub.2 to 5.08,                                               CH.sub.2 Py and 2                                                             lactam-H); 7.35-9.41 (m, 10H, thiazole,                                       C.sub.6 H.sub.5                                                               and Py)                                     41    CH.sub.2 CO.sub.2 K                                                                      4-CH.sub.2 COCH.sub.3                                                                   a (22) 2.55 (s, 3H, CH.sub.3); 3.45 and 3.83                                         (AB, J=19Hz,                                                                  2H, SCH.sub.2); 4.1-4.45 (m, 2H,                                              CH.sub.2); 4.95-6.35                                                          (m, 6H, OCH.sub.2 to 5.08, CH.sub.2 Py                                        and 2 lactam-H);                                                              7.41 (s, 1H, thiazole); 8.11 and 8.96                                         (AA' BB',                                                                     J=6Hz, 4H, Py)                              42    CH.sub.2 CO.sub.2 K                                                                       ##STR112##                                                                             a (24) 1.84 (s, 3H, CH.sub.3); 3.46 and 3.88                                         (AB, J=19Hz, 2H, SCH.sub.2); 3.92-4.55                                        (m, 4H, dioxolan-H); 4.9- 6.35 (m, 6H,                                        OCH.sub.2 to 5.07, CH.sub.2 Py and 2                                          lactam-H); 7.43 (s, 1H, thiazole);                                            7.95.9.36 (m, 3H, Py)                       43    CH.sub.2 CO.sub.2 K                                                                       ##STR113##                                                                             a (18) 1.35-4.05 (m, 11H, cyclopentyl and                                            SCH.sub.2); 4.95- 6.31 (m, 6H,                                                OCH.sub.2 to 5.08, CH.sub.2 Py and 2                                          lactam- H); 7.40 (s, 1H, thiazole);                                           7.85-8.86 (m, 4H, Py)                       44    CH.sub.2 CO.sub.2 K                                                                       ##STR114##                                                                             a (21) 2.05-3.08 (m, 6H, cyclopentyl); 3.43                                          and 3.83 (AB, J=19Hz, 2H, SCH.sub.2);                                         4.9-6.25 (m, 6H, OCH.sub.2 to 5.08,                                           CH.sub.2 Py and 2 lactam-H); 6.81 (bs,                                        1H, cyclopentyl); 7.42 (s, 1H,                                                thiazole); 7.85- 8.91 (m, 4H, Py)           45    CH.sub.2 CO.sub.2 K                                                                       ##STR115##                                                                             a (18) 2.01-2.4 (bs, 8H, cyclopentyl); 3.45                                          and 3.85 (AB, J=19Hz, 2H, SCH.sub.2);                                         4.9-6.15 (m, 6H, OCH.sub.2 to 5.07,                                           CH.sub.2 Py and 2 lactam-H); 7.39 (s,                                         1H, thiazole); 7.98-9.35 (m, 4H, Py)        46    CH.sub.2 CO.sub.2 K                                                                       ##STR116##                                                                             a (25) 1.26-2.31 (m, 10H, CH.sub.2cyclohexyl);                                       2.8-4.05 (m, 3H, CHcyclohexyl,                                                SCH.sub.2); 4.95-6.25 (m, 6H, OCH.sub.2                                       to 5.09, CH.sub.2 Py and 2 lactam-H);                                         7.40 (s, 1H, thiazole); 7.96 and 8.84                                         (AA' BB', J=6Hz, 4H, Py)                    47    CH.sub.2 CO.sub.2 K                                                                       ##STR117##                                                                             a (28) 1.75-2.35 (m, 4H, pyranyl); 3.11-4.12                                         (m, 7H (5 pyranyl-H and SCH.sub.2);                                           4.9-6.28 (m, 6H, OCH.sub.2 to 5.08,                                           CH.sub.2 Py and 2 lactam-H); 7.40 (s,                                         1H,  thiazole); 8.05 and 8.95 (AA' BB',                                       J=6Hz, 4H, Py)                              48    CH.sub.2 CO.sub.2 K                                                                      2-SCH.sub.3                                                                             a (18) 2.95 (s, 3H, SCH.sub.3); 3.41 and 3.81                                        (AB, J=19Hz,                                                                  2H, SCH.sub.2); 4.9-6.35 (m, 6H,                                              OCH.sub.2 to 5.08, CH.sub.2 Py                                                and 2 lactam-H); 7.38 (s, 1H,                                                 thiazole); 7.52-                                                              8.75 (m 4H, Py)                             49    CH.sub.2 CO.sub.2 K                                                                      4-CH.sub.2 SCH.sub.3                                                                    a (14) 2.18 (s, 3H, CH.sub.3); 3.42 and 3.82                                         (AB, J=19Hz,                                                                  2H, SCH.sub.2); 3.95 (s, 2H, CH.sub.2                                         S); 4.9-6.22 (m, 6H,                                                          OCH.sub.2 to 5.08, CH.sub.2 Py and 2                                          lactam-H); 7.36 (s,                                                           1H, thiazole); 8.12 and 8.92 (AA' BB',                                        J=6Hz, 4H, Py)                              50    CH.sub.2 CO.sub.2 K                                                                      3-CH.sub.2 SOCH.sub.3                                                                   a (21) 3.05 (s, 3H, SOCH.sub.3); 3.55 and 3.82                                       (AB, J=19Hz,                                                                  2H, SCH.sub.2); 4.55 (s, 2H, CH.sub.2                                         SO); 4.9-6.45 (m, 6H,                                                         OCH.sub.2 to 5.05, CH.sub.2 Py and 2                                          lactam-H); 7.36 (s,                                                           1H, thiazole); 8.0-9.13 (m, 4H, Py)         51    CH.sub.2 CO.sub.2 K                                                                      3-CH.sub.2 SO.sub.2 CH.sub.3                                                            a (23) 3.35 (s, 3H, SO.sub.2 CH.sub.3); 3.51                                         and 3.85 (AB, J=19Hz,                                                         2H, SCH.sub.2); 4.85 (s, 2H, CH.sub.2                                         SO.sub.2); 4.95-6,36 (m,                                                      6H, OCH.sub.2 to 5.06, CH.sub.2 Py and                                        2 lactam-H); 7.38                                                             (s, 1H, thiazole); 8.03-9.20 (m, 4H,                                          Py)                                         52    CH.sub.2 CO.sub.2 K                                                                      3-F       a (26) 3.51 and 3.88 (AB, J=19Hz, 2H,                                                SCH.sub.2); 5.07 (s,                                                          2H, OCH.sub.2); 5.11-6.48 (m, 4H,                                             CH.sub.2 Py and 2 lactam-                                                     H) 7.41 (s, 1H, thiazole); 7.6-9.25 (m,                                       4H, Py)                                     53    CH.sub.2 CO.sub.2 K                                                                      3-Br4-CH.sub.3                                                                          a (18) 2.83 (s, 3H, CH.sub.3); 3.46 and 3.89                                         (AB, J=19Hz,                                                                  2H, SCH.sub.2); 5.05 (s, 2H,                                                  OCH.sub.2); 5.11-6.42 (m, 4H,                                                 CH.sub.2 Py and 2 lactam-H); 7.41 (s,                                         1H, thiazole);                                                                7.86 (d, J=6Hz, 1H, Py); 8.6-9.2 (m,                                          2H, Py)                                     54    CH.sub.2 CO.sub.2 K                                                                      3-CF.sub.3                                                                              a (30) 3.50 and 3.92 (AB, J=19Hz, 2H,                                                SCH.sub.2); 5.07                                                              (s, 2H, OCH.sub.2); 5.1-6.4 (m, 4H,                                           CH.sub.2 Py and 2                                                             lactam-H); 7.40 (s, 1H, thiazole);                                            8.12-9.55                                                                     (m, 4H, Py)                                 55    CH.sub.2 CO.sub.2 K                                                                       ##STR118##                                                                             a (28) 3.48 and 3.88 (AB, J=19Hz, 2H,                                                SCH.sub.2); 4.9- 6.42 (m, 6H, OCH.sub.2                                       to 5.09, CH.sub.2 Py and 2 lactam-H);                                         7.42 (s, 1H, thiazole); 7.0-9.55 (m,                                          8H, Py)                                     56    CH.sub.2 CO.sub.2 K                                                                      3-(2-Pyridyl)                                                                           a (31) 3.55 and 3.96 (AB, J=19Hz, 2H,                                                SCH.sub.2); 5.05                                                              (s, 2H, OCH.sub.2); 5.23-6.58 (m, 4H,                                         CH.sub.2 Py and                                                               2 lactam-H); 7.40 (s, 1H, thiazole);                                          8.1-9.9                                                                       (m, 8H, Py)                                 57    CH.sub.2 CO.sub.2 CH.sub.3                                                               3-CH.sub.3                                                                              a (28) 2.68 (s, 3H, CH.sub.3); 3.43 and 3.84                                         (AB, J=19Hz,                                                                  2H, SCH.sub.2); 3.95 (s, 3H, CO.sub.2                                         CH.sub.3); 4.85-6.45 (m,                                                      6H, OCH.sub.2 to 5.01, CH.sub.2 Py and                                        2 lactam-H); 7.41                                                             (s, 1H, thiazole); 7.83-9.0 (m, 4H,                                           Py)                                         58    CH.sub.2 CO.sub.2 CH.sub.3                                                               4-OCH.sub.3                                                                             a (27) 3.43 and 3.80 (AB, J=19Hz, 2H,                                                SCH.sub.2); 3.95 (s,                                                          3H, CO.sub.2 CH.sub.3); 4.21 (s, 3H,                                          OCH.sub.3); 4.85-6.25                                                         (m, 6H, OCH.sub.2 to 5.02, CH.sub.2 Py                                        and 2 lactam-H);                                                              7.41 (s, 1H, thiazole); 7.48 and 8.77                                         (AA', BB',                                                                    J=7Hz, 4H, Py)                              59    CH.sub.2 CO.sub.2 CH.sub.3                                                               4-Cyclopropyl                                                                           b (58) 1.1-2.6 (m, 5H, cyclopropyl); 3.42 and                                        3.82                                                                          (AB, J=19Hz, 2H, SCH.sub.2); 3.95 (s,                                         3H,                                                                           CO.sub.2 CH.sub.3); 5.02 (s, 2H,                                              OCH.sub.2); 5.1-6.3 (m, 4H,                                                   CH.sub.2 Py and 2 lactam-H); 7.41 (s,                                         1H, thiazole);                                                                7.66 and 8.70 (AA' BB', J=7Hz, 4H, Py)      60    CH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                        4-Cyclopropyl                                                                           a (31)                                                                                ##STR119##                                                                   7.65 and 8.68 (AA' BB', J=7Hz, 4H, Py)      61    C(CH.sub.3).sub.2 CO.sub.2 K                                                             4-CH.sub.3                                                                              a (31) 1.78 (s, 6H, 2 × CH.sub.3); 2.75                                        (s, 3H, CH.sub.3);                                                            3.43 and 3.82 (AB, J=19Hz, 2H,                                                SCH.sub.2); 5.1-                                                              6.3 (m, 4H, CH.sub.2 Py and 2                                                 lactam-H); 7.33 (s, 1H,                                                       thiazole); 7.87 and 8.74 (AA' BB',                                            J=7Hz, 4H,                                                                    Py)                                         62    C(CH.sub.3).sub.2 CO.sub.2 K                                                             4-C(CH.sub.3).sub.3                                                                     a (29) 1.51 (s, 9H, t-Bu); 1.78 (s, 6H, 2                                            × CH.sub.3);                                                            3.45 and 3.86 (AB, J=19Hz, 2H,                                                SCH.sub.2); 5.15-                                                             6.35 (m, 4H, CH.sub.2 Py and 2                                                lactam-H); 7.38 (s,                                                           1H, thiazole); 8.13 and 8.88 (AA' BB',                                        J=7Hz,                                                                        4H, Py)                                     63    C(CH.sub.3).sub.2 CO.sub.2 K                                                             4-Cyclopropyl                                                                           a (32) 1.15- 2.45 (m, 11H, s,                                                        C(CH.sub.3).sub.2 to 1.77 and                                                 5 cyclopropyl-H); 3.43 and 3.81 (AB,                                          J=19Hz,                                                                       2H, SCH.sub.2); 5.1-6.25 (m, 4H,                                              CH.sub.2 Py and 2                                                             lactam-H); 7.38 (s, 1H, thiazole); 7.65                                       and                                                                           8.68 (AA' BB', J=7Hz, 4H, Py)               64    C(CH.sub.3 ).sub.2 CO.sub.2 K                                                            4-COCH.sub.3                                                                            a (24) 1.79 (s, 6H, 2 × CH.sub.3); 2.90                                        (s, 3H, COCH.sub.3);                                                          3.53 and 3.92 (AB, J=19Hz, 2H,                                                SCH.sub.2); 5.25-                                                             6.5 (m, 4H, CH.sub.2 Py and 2                                                 lactam-H); 7.39 (s,                                                           thiazole); 8.59 and 9.31 (AA' BB',                                            J=7Hz,                                                                        4H, Py)                                     65    C(CH.sub.3).sub.2 CO.sub.2 K                                                             3-OC.sub.2 H.sub.5                                                                      a (32)                                                                                ##STR120##                                                                   1H, thiazole); 7.7-8.75 (m, 4H, Py)         66    C(CH.sub.3).sub.2 CO.sub.2 K                                                             3-OCH(CH.sub.3).sub.2                                                                   a (31)                                                                                ##STR121##                                                                   7.6-8.7 (m, 4H, Py)                         67                                                                                   ##STR122##                                                                              4-Cyclopropyl                                                                           b (52) 1.1-2.6 (m, 5H, cyclopropyl-H); 3.42                                          and 3.83 (AB, J=19Hz, 2H, SCH.sub.2);                                         5.02-6.3 (m, 6H, NOCH.sub.2 to 5.18,                                          CH.sub.2 Py and 2 lactam-H); 6.63-7.16                                        (m, 2H, CCH.sub.2); 7.38 (s, 1H,                                              thiazole); 7.65 and 8.88 (AA' BB',                                            J=7Hz, 4H, Py)                              68                                                                                   ##STR123##                                                                              4-Cyclopropyl                                                                           b (55)                                                                                ##STR124##                                                                   4H, Py)                                     69                                                                                   ##STR125##                                                                              4-Cyclopropyl                                                                           b (38) 1.1-2.8 (m, 11H, cyclobutyl and                                               cyclopropyl-H); 3.40 and 3.80 (AB,                                            J=19Hz, 2H, SCH.sub.2); 5.43 (d, J=                                           5Hz, lactam-H); 5.45 and 5.94 (AB,                                            J=14Hz, 2H, CH.sub.2 Py); 6.12 (d, J=                                         5Hz, lactam-H); 7.42 (s, 1H, thiazole);                                       .65 and 8.71 (AA' BB', J=7Hz, 4H, Py)       70    CH.sub.2 CONH.sub.2                                                                      4-Cyclopropyl                                                                           a (24) 1.0-2.5 (m, 5H, cyclopropyl-H); 3.43                                          and 3.79 (AB, J=19Hz, 2H, SCH.sub.2);                                         5.06 (s, 2H, OCH.sub.2); 5.15-6.30 (m,                                        4H,                                                                           CH.sub.2 Py and 2 lactam-H); 7.43 (s,                                         1H,                                                                           thiazole); 7.63 and 8.73 (AA' , BB',                                          J=                                                                            4H, Py)                                     71    CH.sub.2 CONH.sub.2                                                                      H         a (31))                                                                              3.55 and 3.83 (AB, J=19Hz, 2H,                                                SCH.sub.2);                                                                   5.06 (s, 2H, OCH.sub.2); 5.16-6.25 (m,                                        4H,                                                                           CH.sub.2 Py and 2 lactam-H); 7.41 (s,                                         1H,                                                                           thiazole); 7.7-9.2 (m, 5H, Py)              72    CH.sub.2 CONH.sub.2                                                                      3-CH.sub.2                                                                              a (28) 2.68 (s, 3H, CH.sub.3); 3.48 and 3.78                                         (AB, J=19Hz, 2H, SCH.sub.2); 5.07 (s,                                         2H, OCH.sub.2); 5.16-6.35 (m, 4H,                                             CH.sub.2 Py                                                                   and 2 lactam-H); 7.43 (s, 1H,                                                 thiazole)                                                                     7.72-9.00 (m, 4H, Py)                       73    CH.sub.2 CONH.sub.2                                                                      3-CH.sub.2 OH                                                                           a (34) 3.52 and 3.82 (AB, J=19Hz, 2H,                                                SCH.sub.2); 5.06 (s, 2H, OCH.sub.2);                                          5.20 (s,                                                                      2H, CH.sub.2 OH); 5.1-6.4 (m, 4H,                                             CH.sub.2 Py                                                                   and 2 lactam-H); 7.43 (s, 1H,                                                 thiazole);                                                                    7.72-9.25 (m, 4H, Py)                       74    CH.sub.2 CONH.sub.2                                                                      3-Cl      a (25) 3.55 and 3.88 (AB, J=19Hz, 2H,                                                SCH.sub.2); 5.08 (s, 2H, OCH.sub.2);                                          5.2-6.4 (m,                                                                   4H, CH.sub.2 Py and 2 lactam-H); 7.44                                         (s, 1H,                                                                       thiazole); 7.7-9.25 (m, 4H,                 __________________________________________________________________________                                      Py).                                    

We claim:
 1. A cephem derivative of the formula I ##STR126## and itsphysiologically acceptable acids addition salts in which (A) R¹ denoteshydrogen,(B) R² denotes a group of --CO₂ R³ in which R³ denoteshydrogen, C₁ -C₄ -alkyl, or one equivalent of an alkali metal, alkalineearth metal, or ammonium base, a nitrile group or a carbamoyl group-CONH₂ (C) A denotes (1) a group ##STR127## in which R⁴ and R⁵ can beidentical or different and are individually hydrogen or a C₁ -C₄ -alkylgroup or, ##STR128## (D) B denotes a pyridinium radical ##STR129## whichcan be monosubstituted or disubstituted by identical or different (1) C₁-C₄ alkyl groups,(a) wherein said (C₁ -C₄ alkyl groups can bemonosubstituted by hydroxyl; and (b) wherein two C₁ -C₄ alkyl groups canalso be linked to form a ring that contain 3 to 5 carbon atoms, (2) C₃-C₆ -cycloalkyl, (3) C₁ -C₄ alkoxy; and (4) halogen, and wherein theO--A--R² group in formula (I) is in the syn position, with the provisothat (i) R⁴ and R⁵ cannot both be hydrogen when R³ is hydrogen or a C₁-C₄ alkyl, or (ii) R⁴ and R⁵ cannot be both a C₁ -C₄ alkyl when R³ ishydrogen.
 2. A pharmaceutical formulation which is active againstbacterial infections, containing an effective amount of cephemderivative of the formula I of claim 1 and one or more pharmacologicallyacceptable excipients or diluents.
 3. A method of combatting bacterialinfections comprising the step of administering to a host an effectiveamount of a cephem derivative of the formula I, as defined in claim 1for combatting bacterial infections.